Tri-fused ring compound as well as preparation method and application thereof

Abstract

The invention discloses a tricyclic compound as well as a preparation method and application thereof. In particular, the present invention relates to a compound represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and uses of the compound in drugs for treating chronic kidney disease, renal or cardiac fibrosis, diabetic nephropathy, congestive heart failure, hypertension, primary aldosteronism and Cushing's syndrome, wherein each substituent in the general formula (I) is as defined in the specification.

Description

Tricyclic compounds, preparation methods and applications thereof Technical Field

[0001] The present invention belongs to the field of biomedicine, and specifically relates to a tricyclic compound and a preparation method and application thereof. Background Art

[0002] Aldosterone is a steroid hormone secreted from the adrenal glands that binds to and activates the mineralocorticoid receptor (MR). In primary cells of the distal renal tubules and collecting ducts, MR activation leads to sodium and water retention accompanied by potassium excretion, causing plasma volume expansion and elevated blood pressure (BP). The renin-angiotensin-aldosterone system (RAAS), an endocrine system, regulates blood pressure and fluid balance. Current antihypertensive medications—angiotensin-converting enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRAs)—regulate blood pressure by inhibiting this pathway. Long-term use of ACEi or ARBs can cause an "aldosterone breakthrough," in which aldosterone levels rise after a brief decrease, leading to target organ damage. Currently, the only marketed aldosterone inhibitor, spironolactone, can cause hyperkalemia. Excess aldosterone measured in the circulation is called primary aldosteronism (PA). PA was originally identified in patients with adrenal adenomas, and recent evidence suggests an increased prevalence associated with obesity. PA is a common cause of secondary hypertension, affecting 14% to 21% of patients with resistant hypertension (RHTN), defined as blood pressure that remains above the target blood pressure of 140 / 90 mm Hg despite treatment with a trio of antihypertensive medications (calcium channel blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and diuretics). Refractory hypertension is a high-risk condition associated with a high prevalence of comorbidities, including diabetes, chronic kidney disease, ischemic heart disease, and cerebrovascular disease.

[0003] CYP11B2 is the gene encoding aldosterone synthase, which is highly homologous to the gene sequence encoding cortisol synthase CYP11B1. Developing highly selective CYP11B2 inhibitors to inhibit the synthesis of aldosterone is the main direction for the treatment of refractory hypertension and primary aldosteronism.

[0004] Summary of the Invention

[0005] The object of the present invention is to provide a compound represented by general formula (I'), its stereoisomers or pharmaceutically acceptable salts thereof:

[0006] in:

[0007] is a single bond or a double bond;

[0008] Ring A is phenyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl or absent;

[0009] Ring B is a 4-7 membered heterocyclyl, a 5-6 membered heteroaryl or a phenyl group;

[0010] Ring C is selected from the following groups:

[0011] M1', M2', M4', M5', M6' are each independently selected from N, NH or CH;

[0012] M3 is a bond, N or CH;

[0013] R1 is independently selected from cycloalkyl, heterocyclyl, cycloalkyloxy, heterocyclyloxy, cycloalkylamino, heterocyclylamino, cycloalkylthio, heterocyclylthio, -C(O)(CH2) n R b 、-NR a C(O)(CH2) n R b 、-O(CH2) n R b 、-NH(CH2) n R b 、-S(CH2) n R b 、-S(O)2(CH2) n R b 、-S(O)(NH)(CH2) n R b 、-NR a S(O)2(CH2) n R b 、-NR a S(O)(NH)(CH2) n R b or -NS(O)(CH2) n R a R b Optionally, the cycloalkyl, heterocyclyl, cycloalkyloxy, heterocyclyloxy, cycloalkylamino, heterocyclylamino, cycloalkylthio or heterocyclylthio is further substituted by one or more selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, -C(O)(CH2) n R b 、-S(O)2(CH2) n R b 、-S(O)(NH)(CH2) n R b 、-S(O)2(CH2) n Rb or -NR a S(O)(NH)(CH2) n R b substituted by a substituent in;

[0014] Alternatively, any two R1s form a 3-8 membered cycloalkyl or 4-7 membered heterocyclic group with adjacent carbon atoms, and optionally, the 3-8 membered cycloalkyl or 4-7 membered heterocyclic group is further substituted with an oxo group, -C(O)R b 、-NR a C(O)R b 、-S(O)2R b 、-S(O)(NH)R b 、-NR a S(O)2R b or -NR a S(O)(NH)R b replaced by;

[0015] R a or R b each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, optionally, the cycloalkyl, aryl, heteroaryl or heterocyclyl is further substituted with one or more substituents selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl or -S(O)2alkyl;

[0016] R2, R3 or R4 are each independently selected from hydrogen, deuterium, oxo, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR a C(O)(CH2) n R b or -C(O)NR a (CH2) n R b , which may optionally be further substituted;

[0017] Alternatively, R2 and R3 together with adjacent atoms form a 3-8 membered cycloalkyl, a 5-6 membered heteroaryl or a 4-7 membered heterocyclyl, optionally wherein the 3-8 membered cycloalkyl, the 5-6 membered heteroaryl or the 4-7 membered heterocyclyl is further substituted with one or more substituents selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy or hydroxyalkyl;

[0018] Alternatively, any two R2 form a 3-8 membered cycloalkyl, a 5-6 membered heteroaryl or a 4-7 membered heterocyclyl with adjacent atoms, and the 3-8 membered cycloalkyl, the 5-6 membered heteroaryl or the 4-7 membered heterocyclyl is optionally further substituted with one or more substituents selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy or hydroxyalkyl;

[0019] Alternatively, R2 and R4 form a 5-14 membered cycloalkyl, a 5-14 membered heteroaryl or a 5-14 membered heterocyclyl with adjacent atoms, optionally wherein the 5-14 membered cycloalkyl, the 5-14 membered heteroaryl or the 5-14 membered heterocyclyl is further substituted with one or more substituents selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy or hydroxyalkyl;

[0020] p, x, y and z are each independently selected from 1, 2, 3 or 4;

[0021] n is selected from 0, 1, 2 or 3.

[0022] In a preferred embodiment of the present invention, R1 is independently selected from 3-8 membered cycloalkyl, 4-8 membered heterocyclyl, 3-8 membered cycloalkyloxy, 4-8 membered heterocyclyloxy, 3-8 membered cycloalkylamino, 4-8 membered heterocyclylamino, 3-8 membered cycloalkylthio, 4-8 membered heterocyclylthio, -C(O)(CH2) n R b 、-NR a C(O)(CH2) n R b 、-O(CH2) n R b 、-NH(CH2) n R b 、-S(CH2) n R b 、-S(O)2(CH2) n R b 、-S(O)(NH)(CH2) n R b 、-NR a S(O)2(CH2)n R b or -NR a S(O)(NH)(CH2) n R b Optionally, the 3-8 membered cycloalkyl, 4-8 membered heterocyclyl, 3-8 membered cycloalkyloxy, 4-8 membered heterocyclyloxy, 3-8 membered cycloalkylamino, 4-8 membered heterocyclylamino, 3-8 membered cycloalkylthio, 4-8 membered heterocyclylthio are further substituted by one or more selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)(CH2) n R b 、-S(O)2(CH2) n R b 、-S(O)(NH)(CH2) n R b 、-S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b substituted by a substituent in;

[0023] R a or R b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, 3-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 selected from C (O), N, O or S or 4-8 membered heterocyclic group containing 1-3 selected from C (O), N, O or S, optionally, the 3-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 selected from C (O), N, O or S or 4-8 membered heterocyclic group containing 1-3 selected from C (O), N, O or S is further substituted by one or more selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, 3-6 membered cycloalkyl or -SO2-C 1-6 substituted by a substituent in the alkyl group.

[0024] In a preferred embodiment of the present invention, R1 is independently selected from 3-8 membered cycloalkyl, 4-8 membered heterocyclyl containing 1-3 groups selected from N, O, S, SO2 or SONH, 3-8 membered cycloalkyloxy, 3-8 membered cycloalkylamino, 4-8 membered heterocyclyloxy containing 1-3 groups selected from N, O, S, SO2 or SONH, 4-8 membered heterocyclylamino containing 1-3 groups selected from N, O, S, SO2 or SONH, -C(O)(CH2) n R b 、-NR a C(O)(CH2) n R b 、-O(CH2) n R b 、-S(O)2(CH2) n R b 、-S(O)(NH)(CH2) n R b 、-NR a S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b , optionally, the 3-8 membered cycloalkyl, the 4-8 membered heterocyclyl containing 1-3 selected N, O, S, SO2 or SONH, the 3-8 membered cycloalkyloxy, the 3-8 membered cycloalkylamino, the 4-8 membered heterocyclyloxy containing 1-3 selected N, O, S, SO2 or SONH or the 4-8 membered heterocyclylamino containing 1-3 selected N, O, S, SO2 or SONH are further substituted by one or more selected oxo groups, -C(O)(CH2) n R b 、-S(O)2(CH2) n R b 、-S(O)(NH)(CH2) n R b 、-S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b substituted by a substituent in;

[0025] R a or R b are each independently selected from hydrogen, deuterium, C 1-3 alkyl, 3-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 selected from N, O or S or 4-8 membered heterocyclic group containing 1-3 selected from C (O), N, O or S, optionally, the 5-8 membered heteroaryl containing 1-3 selected from N, O or S or the 4-8 membered heterocyclic group containing 1-3 selected from C (O), N, O or S are further substituted by one or more selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, 3-6 membered cycloalkyl or -SO2-C 1-3 substituted by a substituent in the alkyl group.

[0026] In a preferred embodiment of the present invention, R2, R3 or R4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1- 6-halogenated alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Hydroxyalkyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkyloxy, 3-8 membered cycloalkylamino, C 6-10 Aryl, 5-6 membered heteroaryl containing 1-3 selected from N, O, S or 4-8 membered heterocyclic group containing 1-3 selected from C(O), N, O or S, -NR a R b 、-NR a C(O)R b or -C(O)NR a R b .

[0027] In a preferred embodiment of the present invention, R2, R3 or R4 are each independently selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl or C3-6 Cycloalkyloxy.

[0028] In a preferred embodiment of the present invention, Selected from the following groups:

[0029] The object of the present invention is to provide a compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof:

[0030] in:

[0031] Ring A is selected from phenyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl or absent;

[0032] Ring B is selected from 4-7 membered heterocyclyl, 5-6 membered heteroaryl or phenyl;

[0033] Ring C is selected from 4-7 membered cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;

[0034] M1, M2 or M3 are each independently selected from N or CR4;

[0035] R1 is independently selected from cycloalkyl, heterocyclyl, cycloalkyloxy, heterocyclyloxy, cycloalkylamino, heterocyclylamino, cycloalkylthio, heterocyclylthio, -C(O)(CH2) n R b 、-NR a C(O)(CH2) n R b 、-O(CH2) n R b 、-NH(CH2) n R b 、-S(CH2) n R b 、-S(O)2(CH2) n R b 、-S(O)(NH)(CH2) n R b 、-NR a S(O)2(CH2) n R b 、-NR a S(O)(NH)(CH2) n R b or -NS(O)(CH2) n R a R bOptionally, the cycloalkyl, heterocyclyl, cycloalkyloxy, heterocyclyloxy, cycloalkylamino, heterocyclylamino, cycloalkylthio or heterocyclylthio is further substituted by one or more selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, -C(O)(CH2) n R b 、-S(O)2(CH2) n R b 、-S(O)(NH)(CH2) n R b 、-S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b substituted by a substituent in;

[0036] R a or R b each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, optionally, the cycloalkyl, aryl, heteroaryl or heterocyclyl is further substituted with one or more substituents selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl or -S(O)2alkyl;

[0037] R2, R3 or R4 are each independently selected from hydrogen, deuterium, oxo, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR a C(O)(CH2) n R b or -C(O)NR a (CH2) n R b , which may optionally be further substituted;

[0038] Alternatively, R2 and R3 together with adjacent atoms form a 3-8 membered cycloalkyl, a 5-6 membered heteroaryl or a 4-7 membered heterocyclyl, optionally wherein the 3-8 membered cycloalkyl, the 5-6 membered heteroaryl or the 4-7 membered heterocyclyl is further substituted with one or more substituents selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy or hydroxyalkyl;

[0039] x, y and z are each independently selected from 0, 1, 2, 3 or 4;

[0040] n is selected from 0, 1, 2 or 3.

[0041] In a preferred embodiment of the present invention, ring A is selected from a 5-7 membered heterocyclic group or a 5-6 membered heteroaryl group containing 1-3 groups selected from C(O), N, O, S, SO2 or SONH.

[0042] In a preferred embodiment of the present invention, ring B is selected from phenyl, containing 1-3 5-7 membered heterocyclic groups or 5-6 membered heteroaryl groups selected from C(O), N, O or S.

[0043] In a preferred embodiment of the present invention, ring C is selected from 4-6 membered cycloalkyl, phenyl, 5-7 membered heterocyclic group containing 1-3 atoms selected from N, O or S, or 5-6 membered heteroaryl.

[0044] In a preferred embodiment of the present invention, Selected from

[0045] In a preferred embodiment of the present invention, R1 is independently selected from 3-10 membered cycloalkyl, 4-10 membered heterocyclyl, 3-8 membered cycloalkyloxy, 4-8 membered heterocyclyloxy, 3-8 membered cycloalkylamino, 4-8 membered heterocyclylamino, 3-8 membered cycloalkylthio, 4-8 membered heterocyclylthio, -C(O)(CH2) n R b 、-NR a C(O)(CH2) n R b 、-O(CH2) n R b 、-NH(CH2) n R b 、-S(CH2) n R b 、-S(O)2(CH2) n R b 、-S(O)(NH)(CH2) n R b 、-NR aS(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b Optionally, the 3-10 membered cycloalkyl, 4-10 membered heterocyclyl, 3-8 membered cycloalkyloxy, 4-8 membered heterocyclyloxy, 3-8 membered cycloalkylamino, 4-8 membered heterocyclylamino, 3-8 membered cycloalkylthio, 4-8 membered heterocyclylthio are further substituted by one or more selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)(CH2) n R b 、-S(O)2(CH2) n R b 、-S(O)(NH)(CH2) n R b 、-S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b substituted by a substituent in;

[0046] R a or R b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, 3-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 selected from C (O), N, O or S or 4-8 membered heterocyclic group containing 1-3 selected from C (O), N, O or S, optionally, the 3-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 selected from C (O), N, O or S or 4-8 membered heterocyclic group containing 1-3 selected from C (O), N, O or S is further substituted by one or more selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl or -SO2-C 1-6 substituted by a substituent in the alkyl group.

[0047] In a preferred embodiment of the present invention, R a or R b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1- 6-halogenated alkoxy, C 1-6 Hydroxyalkyl, 3-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 selected from C (O), N, O or S or 4-8 membered heterocyclic group containing 1-3 selected from C (O), N, O or S, optionally, the 3-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 selected from C (O), N, O or S or 4-8 membered heterocyclic group containing 1-3 selected from C (O), N, O or S is further substituted by one or more selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1- 6-hydroxyalkyl, 3-6-membered cycloalkyl or -SO2-C 1-6 substituted by a substituent in the alkyl group.

[0048] In a preferred embodiment of the present invention, R1 is independently selected from 3-10 membered cycloalkyl, 4-10 membered heterocyclyl containing 1-3 selected N, O, S, SO2 or SONH, 3-8 membered cycloalkyloxy, 4-8 membered heterocyclyloxy containing 1-3 selected N, O, S, SO2 or SONH, -C(O)(CH2) n R b 、-NR a C(O)(CH2) n R b 、-O(CH2) n R b 、-S(O)2(CH2) nR b 、-S(O)(NH)(CH2) n R b 、-NR a S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b Optionally, the 3-10 membered cycloalkyl, the 4-10 membered heterocyclyl containing 1-3 selected N, O, S, SO2 or SONH, the 3-8 membered cycloalkyloxy, the 4-8 membered heterocyclyloxy containing 1-3 selected N, O, S, SO2 or SONH is further substituted by one or more selected oxo groups, -C(O)(CH2) n R b 、-S(O)2(CH2) n R b 、-S(O)(NH)(CH2) n R b 、-S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b substituted by a substituent in;

[0049] R a or R b are each independently selected from hydrogen, deuterium, C 1-3 alkyl, 3-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 selected from N, O or S or 4-8 membered heterocyclic group containing 1-3 selected from C (O), N, O or S, optionally, the 5-8 membered heteroaryl containing 1-3 selected from N, O or S or the 4-8 membered heterocyclic group containing 1-3 selected from C (O), N, O or S are further substituted by one or more selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl or -SO2-C 1-3 substituted by a substituent in the alkyl group.

[0050] In a preferred embodiment of the present invention, R1 is independently selected from 3-8 membered cycloalkyl, 4-8 membered heterocyclyl, 3-8 membered cycloalkyloxy, 4-8 membered heterocyclyloxy, 3-8 membered cycloalkylamino, 4-8 membered heterocyclylamino, 3-8 membered cycloalkylthio, 4-8 membered heterocyclylthio, -C(O)(CH2) n R b 、-NR a C(O)(CH2) n R b 、-S(O)2(CH2) n R b 、-S(O)(NH)(CH2) n R b 、-NR a S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b Optionally, the 3-8 membered cycloalkyl, 4-8 membered heterocyclyl, 3-8 membered cycloalkyloxy, 4-8 membered heterocyclyloxy, 3-8 membered cycloalkylamino, 4-8 membered heterocyclylamino, 3-8 membered cycloalkylthio, 4-8 membered heterocyclylthio are further substituted by one or more selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -C(O)(CH2) n R b 、-S(O)2(CH2) n R b 、-S(O)(NH)(CH2) n R b 、-S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b substituted by a substituent in;

[0051] R a or R b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 hydroxyalkyl, 3-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 selected from C(O), N, O or S, or 4-8 membered heterocyclyl containing 1-3 selected from C(O), N, O or S.

[0052] In a preferred embodiment of the present invention, R1 is independently selected from 3-8 membered cycloalkyl, 4-8 membered heterocyclyl containing 1-3 selected N, O, S, SO2 or SONH, 3-8 membered cycloalkyloxy, 3-8 membered cycloalkylamino, 4-8 membered heterocyclyloxy containing 1-3 selected N, O, S, SO2 or SONH, 4-8 membered heterocyclylamino containing 1-3 selected N, O, S, SO2 or SONH, -C(O)(CH2) n R b 、-NR a C(O)(CH2) n R b 、-O(CH2) n R b 、-S(O)2(CH2) n R b 、-S(O)(NH)(CH2) n R b 、-NR a S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b , optionally, the 3-8 membered cycloalkyl, the 4-8 membered heterocyclyl containing 1-3 selected N, O, S, SO2 or SONH, the 3-8 membered cycloalkyloxy, the 3-8 membered cycloalkylamino, the 4-8 membered heterocyclyloxy containing 1-3 selected N, O, S, SO2 or SONH or the 4-8 membered heterocyclylamino containing 1-3 selected N, O, S, SO2 or SONH are further substituted by one or more selected oxo groups, -C(O)(CH2) n R b 、-S(O)2(CH2) n R b 、-S(O)(NH)(CH2) n R b 、-S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R bsubstituted by a substituent in;

[0053] R a or R b are each independently selected from hydrogen, deuterium, C 1-3 alkyl, 3-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 selected from N, O or S or 4-8 membered heterocyclic group containing 1-3 selected from C (O), N, O or S, optionally, the 5-8 membered heteroaryl containing 1-3 selected from N, O or S or the 4-8 membered heterocyclic group containing 1-3 selected from C (O), N, O or S are further substituted by one or more selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, 3-6 membered cycloalkyl or -SO2-C 1-3 substituted by a substituent in the alkyl group.

[0054] In a preferred embodiment of the present invention, R1 is independently selected from 3-8 membered cycloalkyl, 4-8 membered heterocyclyl containing 1-3 selected N, O, S, SO2 or SONH, 3-8 membered cycloalkyloxy, 4-8 membered heterocyclyloxy containing 1-3 selected N, O, S, SO2 or SONH, -C(O)(CH2) n R b 、-NR a C(O)(CH2) n R b 、-S(O)2(CH2) n R b 、-S(O)(NH)(CH2) n R b 、-NR a S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b Optionally, the 3-8 membered cycloalkyl, the 4-8 membered heterocyclyl containing 1-3 selected N, O, S, SO2 or SONH, the 3-8 membered cycloalkyloxy, the 4-8 membered heterocyclyloxy containing 1-3 selected N, O, S, SO2 or SONH is further substituted by one or more selected oxo groups, -C(O)(CH2) n R b 、-S(O)2(CH2) n Rb 、-S(O)(NH)(CH2) n R b 、-S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b substituted by a substituent in;

[0055] In a preferred embodiment of the present invention, R2, R3 or R4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Hydroxyalkyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkyloxy, 3-8 membered cycloalkylamino, C 6-10 Aryl, 5-6 membered heteroaryl containing 1-3 selected from N, O, S or 4-8 membered heterocyclic group containing 1-3 selected from C(O), N, O or S, -NR a R b 、-NR a C(O)R b or -C(O)NR a R b .

[0056] In a preferred embodiment of the present invention, R2, R3 or R4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, 3-8 membered cycloalkyl or 4-8 membered heterocyclic group containing 1-3 selected from C(O), N, O or S, -NR a C(O)R b or -C(O)NR a R b ;

[0057] R a or R b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 hydroxyalkyl, 3-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 selected from C(O), N, O or S, or 4-8 membered heterocyclyl containing 1-3 selected from C(O), N, O or S.

[0058] In a preferred embodiment of the present invention, R2, R3 or R4 are each independently selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl or C 3-6 Cycloalkyloxy.

[0059] In a preferred embodiment of the present invention, R2, R3 or R4 are each independently selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy or C 1-3 Hydroxyalkyl.

[0060] In a more preferred embodiment of the present invention, the general formula (I) is further a compound represented by general formula (Ia)-(Ii), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0061] M1, M2 or M3 are each independently selected from N or CH;

[0062] R1 is each independently selected from NR a C(O)R b , 3-8 membered cycloalkyl, 4-8 membered heterocyclyl containing 1-3 selected N, O, S, SO2 or SONH, 3-8 membered cycloalkyloxy, 4-8 membered heterocyclyloxy containing 1-3 selected N, O, S, SO2 or SONH;

[0063] R2 are each independently selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C1-3 Hydroxyalkyl or C 3-6 Cycloalkyl;

[0064] R a Selected from hydrogen, deuterium, C 1-3 Alkyl or C 1-3 deuterated alkyl;

[0065] R b Selected from hydrogen, deuterium, C 1-3 alkyl, 3-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 selected from N, O or S, or 4-8 membered heterocyclic group containing 1-3 selected from C(O), N, O, S, SO2 or SONH, optionally, the C 1-3 Alkyl, 3-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 selected from N, O or S or 4-8 membered heterocyclic group containing 1-3 selected from C(O), N, O, S, SO2 or SONH, further substituted by hydroxyl, amino, CN, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Substituted by hydroxyalkyl or 3-6 membered cycloalkyl;

[0066] y is 1, 2, or 3.

[0067] In a more preferred embodiment of the present invention, the general formula (I) is further a compound represented by the general formula (II-a)-(II-n), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0068] in:

[0069] M4 are each independently selected from O or CH2;

[0070] R1 is each independently selected from -C(O)R b 、-NR a C(O)R b 、-OR b 、-S(O)2R b 、-S(O)(NH)R b 、-NR a S(O)2R b 、-NR a S(O)(NH)R b or a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally further substituted with an oxo group, a halogen group, a hydroxyl group, a cyano group, a C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Deuterated alkyl, C1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Preferably, the 4-8 membered heterocyclic group contains 1-3 selected from N, O, S, SO2 or SONH, optionally further substituted by oxo, halogen, hydroxyl, cyano, C 1-3 Alkyl, C 3-6 Cycloalkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy or C 1-3 substituted by one or more haloalkoxy groups;

[0071] R a or R b are independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 3-8 Cycloalkyl, 5-8 membered heteroaryl containing 1-3 selected from N, O or S or 4-8 membered heterocyclic group containing 1-3 selected from C(O), N, O or S, optionally, the hydroxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, 3-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 selected from N, O or S, or 4-8 membered heterocyclic group containing 1-3 selected from C(O), N, O or S, further substituted with hydroxyl, amino, CN, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Substituted by hydroxyalkyl or 3-6 membered cycloalkyl;

[0072] R2 are each independently selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl or C 3-6 Cycloalkyl.

[0073] In a more preferred embodiment of the present invention, R1 is independently selected from -C(O)Rb 、-NR a C(O)R b 、-OR b 、-S(O)2R b 、-S(O)(NH)R b 、-NR a S(O)2R b 、-NR a S(O)(NH)R b or a 4-8 membered nitrogen-containing heterocyclic group, wherein the 4-8 membered nitrogen-containing heterocyclic group is optionally further -C(O)R b or -S(O)2R b replaced.

[0074] On the other hand, the present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of any compound of the general formula shown, its stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0075] In certain embodiments of the present invention, the pharmaceutical composition, calculated as the free base, has a weight percentage of the compound, its stereoisomer or a pharmaceutically acceptable salt thereof of 0.1% to 95%, preferably 5% to 70%, for example 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10% or 5%.

[0076] In certain embodiments of the present invention, the pharmaceutical composition is selected from tablets, capsules, liquid preparations or injections, and preferably further comprises a filler, optionally a disintegrant, or further comprises one or more of a glidant or a lubricant.

[0077] In certain embodiments of the present invention, the pharmaceutical composition is a rapid-release formulation or a sustained-release formulation.

[0078] In certain embodiments of the present invention, the pharmaceutical composition, calculated as the free base, the unit dose of the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is 1-1000 mg, preferably 1-500 mg, or preferably 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 200 mg, 300 mg, 400 mg or 500 mg.

[0079] In certain embodiments of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof, can be administered by any convenient method, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, intrathecal or transdermal administration, and the pharmaceutical composition adjusted accordingly.

[0080] In certain embodiments of the present invention, the compound, its stereoisomers or pharmaceutically acceptable salts thereof can be formulated into liquid or solid preparations, such as syrups, suspensions, emulsions, tablets, capsules, powders, granules, or lozenges.

[0081] On the other hand, the present invention further relates to the use of any compound of the general formula shown, its stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical composition in the preparation of drugs for treating diseases related to CYP11B2.

[0082] The present invention further relates to the use of the compound represented by the general formula, its stereoisomers or pharmaceutically acceptable salts, or its pharmaceutical composition in the preparation of drugs for treating or preventing chronic kidney disease, renal or cardiac fibrosis, diabetic nephropathy, congestive heart failure, hypertension, primary aldosteronism and Cushing's syndrome.

[0083] In a preferred embodiment of the present invention, the hypertension is refractory hypertension.

[0084] In some embodiments, the compounds of the present invention have an EC of 0. 50 The values ​​range from 0.0001 μM to 50 μM; the EC values ​​of the preferred compounds for CYP11B2 50 The values ​​are between 0.0001 μM and 10 μM; more preferred compounds have an EC value for CYP11B2 50 The value is between 0.0001 μM and 1 μM; further preferred compounds have an EC value of 50 The values ​​ranged from 0.0001 μM to 0.1 μM.

[0085] At the same time, the compounds of the present invention have good selectivity for CYP11B1, with a selectivity greater than 50, preferably the selectivity of the compounds greater than 100, more preferably the selectivity of the compounds greater than 200, and further preferably the selectivity of the compounds greater than 500.

[0086] The compounds of the present invention also have good pharmacokinetic properties, especially deuterated compounds, which have higher metabolic stability in the liver, kidneys, and plasma, higher in vivo exposure, and exhibit very high bioavailability. In addition, they also have better safety and a higher safety window.

[0087] Detailed Description of the Invention

[0088] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0089] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3- Methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl , 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups. Methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl are preferred.

[0090] The term "alkylene" refers to an alkyl group in which one hydrogen atom is further substituted, for example: "methylene" refers to -CH2-, "ethylene" refers to -(CH2)2-, "propylene" refers to -(CH2)3-, "butylene" refers to -(CH2)4-, etc. The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example, ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. The alkenyl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0091] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0092] The term "spiroalkyl" refers to a polycyclic group having a carbon atom (called a spiral atom) shared between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiral atoms shared between the rings, the spiroalkyl is divided into a single spiroalkyl, a double spiroalkyl or a multi-spiroalkyl, preferably a single spiroalkyl and a double spiroalkyl. More preferably, it is 3 yuan / 6 yuan, 3 yuan / 5 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan of single spiroalkyl. Non-limiting examples of spiroalkyl include:

[0093] wait;

[0094] It also includes spirocycloalkyl groups that share a spiro atom with a heterocycloalkyl group. Non-limiting examples include:

[0095] wait.

[0096] The term "fused cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with the other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl groups. Non-limiting examples of fused cycloalkyl groups include: wait.

[0097] The term "bridged cycloalkyl" refers to a 5-20 membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6-14 members, more preferably 7-10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged cycloalkyl groups include:

[0098] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0099] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms; most preferably, it contains 3 to 8 ring atoms; further preferably, it is a 3-8 membered heterocyclic group containing 1-3 nitrogen atoms, optionally substituted with 1-2 oxygen atoms, sulfur atoms, or oxo groups, including nitrogen-containing monocyclic heterocyclic groups, nitrogen-containing spiro heterocyclic groups, or nitrogen-containing fused heterocyclic groups.

[0100] Non-limiting examples of monocyclic heterocyclic groups include azetidine, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azepanyl, 1,4-diazepanyl, pyranyl, etc., preferably pyrrolidinyl, morpholinyl, piperidinyl, azepanyl, 1,4-diazepanyl and piperazinyl. Polycyclic heterocyclic groups include spirocyclic, fused ring and bridged heterocyclic groups; wherein the spirocyclic, fused ring and bridged heterocyclic groups are optionally connected to other groups by a single bond, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups by any two or more atoms on the ring.

[0101] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which the monocyclic rings of 5 to 20 members share one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer 0 to 2) heteroatom, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of shared spiral atoms between the rings, the spiral heterocyclic group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiral heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic group. More preferably 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral heterocyclic group. Non-limiting examples of spiral heterocyclic groups include:

[0102] wait.

[0103] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, wherein each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0104] wait.

[0105] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged heterocyclic groups include:

[0106] wait.

[0107] The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

[0108] wait.

[0109] The heterocyclyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0110] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. More preferably, phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, including benzo 5- to 10-membered heteroaryl, benzo 3- to 8-membered cycloalkyl, and benzo 3- to 8-membered heteroalkyl, preferably benzo 5- to 6-membered heteroaryl, benzo 3- to 6-membered cycloalkyl, and benzo 3- to 6-membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms; or further comprises a three-membered nitrogen-containing fused ring containing a benzene ring.

[0111] Wherein the ring connecting to the parent structure is an aryl ring, non-limiting examples of which include:

[0112] wait.

[0113] The aryl group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0114] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 12-membered, more preferably 5-membered or 6-membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl or thiazolyl; more preferably pyrazolyl, pyrrolyl and oxazolyl. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0115] wait.

[0116] The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0117] The term "alkoxy" refers to-O-(alkyl) and-O-(unsubstituted cycloalkyl), wherein the definition of alkyl is as described above. The limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, substituents are preferably one or more following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0118] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0119] "Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0120] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0121] "Alkenyl" refers to an alkenyl group, also known as an alkene group, which refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond and the carbon-carbon double bond can be located at any position within the alkenyl group. The alkenyl group is a group having 2 to 20 (C 2-20 ), 2 to 15 (C 2- 15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ), 2 to 4 (C 2-4 ) or 2 to 3 (C 2-3 ) carbon atoms. Non-limiting examples of alkenyl groups include: The alkenyl group can be further substituted by other related groups, for example, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0122] "Alkynyl" refers to (CH≡C-), which contains at least one carbon-carbon triple bond and the carbon-carbon triple bond can be located at any position within the alkynyl group, which contains at least one carbon-carbon double bond and the carbon-carbon double bond can be located at any position within the alkenyl group, and the alkynyl group is a group having 2 to 20 (C 2- 20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ), 2 to 4 (C 2-4 ) or 2 to 3 (C 2-3 ) carbon atoms. Non-limiting examples of alkynyl groups include: The alkynyl group can be further substituted by other related groups, for example, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0123] The term "alkenylcarbonyl" refers to -C(O)-(alkenyl), wherein the definition of alkenyl is as described above. Non-limiting examples of alkenylcarbonyl include: vinylcarbonyl, propenylcarbonyl, butenylcarbonyl. Alkenylcarbonyl can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0124] Refers to a single bond or a double bond.

[0125] "Hydroxy" refers to an -OH group.

[0126] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0127] "Amino" refers to -NH2.

[0128] "Cyano" refers to -CN.

[0129] "Nitro" refers to -NO2.

[0130] "Carbonyl" refers to -C(O)-.

[0131] "Carboxyl" refers to -C(O)OH.

[0132] "THF" refers to tetrahydrofuran.

[0133] "MeOH" refers to methanol.

[0134] "DMF" refers to N,N-dimethylformamide.

[0135] "TFA" refers to trifluoroacetic acid.

[0136] "MeCN" refers to acetylene glycol.

[0137] "DMA" refers to N,N-dimethylacetamide.

[0138] Different expressions such as “X is selected from A, B, or C”, “X is selected from A, B and C”, “X is A, B or C”, and “X is A, B and C” all express the same meaning, that is, X can be any one or more of A, B, and C.

[0139] The hydrogen atoms described in the present invention can all be replaced by their isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.

[0140] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0141] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0142] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0143] "Pharmaceutically acceptable salt" and "pharmaceutically usable salt" refer to salts of the compounds of the present invention, which are safe and effective when used in mammals and have the desired biological activity. DETAILED DESCRIPTION

[0144] Example

[0145] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and tetramethylsilane (TMS) as the internal standard.

[0146] MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

[0147] HPLC analysis was performed using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150×4.6 mm column).

[0148] Average kinase inhibition rate and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG, Germany).

[0149] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0150] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0151] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, and other companies.

[0152] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0153] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0154] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0155] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0156] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0157] A CEM DiscoverS 908860 microwave reactor was used for the microwave reaction.

[0158] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0159] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0160] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent systems used in the reactions were: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, and D: acetone. The volume ratio of the solvents was adjusted according to the polarity of the compounds.

[0161] The eluent system for column chromatography and the developing solvent system for thin-layer chromatography used to purify the compound include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: dichloromethane and acetone system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0162] intermediates

[0163] Intermediate Im-1

[0164] first step

[0165] 5-Bromo-4-methyl-pyridine-3-carboxylic acid (20 g, 92.58 mmol) was dissolved in anhydrous N,N-dimethylformamide (200 mL), and anhydrous ethanol (42.65 g, 925.79 mmol, 54.06 mL), HATU (52.39 g, 138.87 mmol), and TEA (28.10 g, 277.74 mmol, 38.74 mL) were added. The reaction system was stirred at room temperature (20°C) for 16 hours. After completion, water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL x 3), washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, and filtered and concentrated to obtain crude 5-bromo-4-methyl-pyridine-3-carboxylic acid ethyl ester (21 g, crude).

[0166] MS m / z(ESI): 244.0, 246.0[M+1].

[0167] Step 2

[0168] 5-Bromo-4-methyl-pyridine-3-carboxylic acid ethyl ester (7 g, 28.68 mmol) was dissolved in anhydrous tetrahydrofuran (200 mL), and lithium diisopropylamide (2 M, 17.21 mL) was added dropwise thereto at -78 ° C. and stirred at -78 ° C for 1 hour. Then, methyl acrylate (6.17 g, 71.70 mmol, 6.46 mL) was slowly added thereto. The reaction system was naturally warmed to room temperature and stirred for 5 hours. After completion of the reaction, water (20 mL) was slowly added dropwise thereto to quench the reaction, extracted with ethyl acetate (50 mL x 3), washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by column chromatography (PE / EtOAc=3:1, uv=254 nm) to obtain methyl 4-bromo-8-carbonyl-6,7-dihydro-5H-isoquinoline-7-carboxylate (4 g, 14.0 mmol, 48.8% yield).

[0169] MS m / z(ESI): 284.0, 286.0[M+1].

[0170] Step 3

[0171] Dissolve methyl 4-bromo-8-carbonyl-6,7-dihydro-5H-isoquinoline-7-carboxylate (7 g, 24.64 mmol) in 6 M hydrochloric acid (30 mL). Stir the reaction system in an oil bath at 100°C for 2 hours. After completion, cool to room temperature and adjust the pH to 7-8 with 6 M sodium hydroxide solution. Wash with ethyl acetate (50 mL x 3) and saturated brine (50 mL x 2), dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product 4-bromo-6,7-dihydro-5H-isoquinolin-8-one (4.8 g, 21.23 mmol, 86.17% yield). This crude product was used directly in the next reaction.

[0172] MS m / z(ESI): 226.0, 228.0[M+1].

[0173] Step 4

[0174] Dissolve 4-bromo-6,7-dihydro-5H-isoquinolin-8-one (7 g, 30.96 mmol) in ammonia-methanol solution (2 M, 100 mL) and add tetraisopropyl titanate (17.60 g, 61.93 mmol, 18.33 mL). After stirring the reaction system at 20 ° C for 16 hours, sodium borohydride (1.76 g, 46.45 mmol) was added in batches in an ice-water bath. The reaction system was stirred at room temperature for 2 hours. After the reaction was completed, water (20 mL) was added.

[0175] The reaction was quenched, filtered through celite, extracted with ethyl acetate (50 mL x 3), washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (Dichloromethane:Methanol = 10:1, UV = 254 nm) to afford 4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine (4.5 g, 19.82 mmol, 63.99% yield).

[0176] MS m / z(ESI): 227.0, 229.0[M+1].

[0177] Step 5

[0178] (R)-4-Bromo-5,6,7,8-tetrahydroisoquinolin-8-amine

[0179] 4-Bromo-5,6,7,8-tetrahydroisoquinolin-8-amine (4.5 g, 19.82 mmol) was subjected to the following chiral separation to obtain P1 and Im-1 products, respectively.

[0180] MS m / z(ESI): 227.0, 229.0[M+1].

[0181] Intermediate 2

[0182] first step

[0183] 6-Bromo-3,4-dihydro-1H-quinolin-2-one (10 g, 44.23 mmol) was dissolved in DMF (100 mL). Potassium tert-butoxide (9.93 g, 88.47 mmol) was slowly added in an ice-water bath. After stirring for 0.5 hours, iodomethane (9.62 g, 66.35 mmol) was added dropwise. The reaction system was stirred at room temperature (20°C) for 5.5 hours. After completion of the reaction, H2O (20 mL) was slowly added in an ice-water bath to quench the reaction. The product was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude 6-bromo-1-methyl-3,4-dihydroquinolin-2-one (10 g, crude).

[0184] MS m / z(ESI): 239.9, 241.9[M+H].

[0185] Step 2

[0186] Dissolve 6-bromo-1-methyl-3,4-dihydroquinolin-2-one (10 g, 41.65 mmol) in 1,4-dioxane (100 mL), and add pinacol diboronate (12.69 g, 49.98 mmol), potassium acetate (8.18 g, 83.30 mmol), and Pd(dppf)Cl2 (3.02 g, 4.16 mmol). The reaction system was purged with nitrogen several times and stirred in an oil bath at 80°C for 16 hours. After completion of the reaction, cool to room temperature, dilute with water, wash with saturated brine, dry over anhydrous sodium sulfate, and filter and concentrate to obtain the crude product. The crude product was purified by column chromatography (PE / EtOAc=3:1, UV=254 nm) to give 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2-one (10 g, 83.6% yield).

[0187] MS m / z(ESI):288.2[M+H].

[0188] Intermediate 3

[0189] first step

[0190] 6-Bromo-3,4-dihydro-1H-quinolin-2-one (10 g, 44.23 mmol) was dissolved in DMF (100 mL). Potassium tert-butoxide (9.93 g, 88.47 mmol) was slowly added in an ice-water bath. After 0.5 hour, deuterated iodomethane (9.62 g, 66.35 mmol) was added dropwise. The reaction system was stirred at room temperature (20°C) for 5.5 hours. After completion of the reaction, H2O (20 mL) was slowly added in an ice-water bath to quench the reaction. The product was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product 6-bromo-1-(methyl-d3)-3,4-dihydroquinolin-2-one (10 g, crude).

[0191] MS m / z(ESI): 243.0, 245.0[M+H].

[0192] Step 2

[0193] Dissolve 6-bromo-1-(methyl-d3)-3,4-dihydroquinolin-2-one (10 g, 41.13 mmol) in 1,4-dioxane (100 mL), and add pinacol diboronate (12.53 g, 49.36 mmol), potassium acetate (8.07 g, 82.27 mmol), and Pd(dppf)Cl2 (2.98 g, 4.11 mmol). The reaction system was purged with nitrogen several times and stirred in an oil bath at 80°C for 16 hours. After completion of the reaction, cool to room temperature, dilute with water, wash with saturated brine, dry over anhydrous sodium sulfate, and filter and concentrate to obtain the crude product. The crude product was purified by column (PE / EtOAc=3:1, UV=254 nm) to give 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(methyl-d3)-3,4-dihydroquinolin-2-one (10 g, 83% yield).

[0194] MS m / z(ESI):291.2[M+H].

[0195] Intermediate 4

[0196] first step

[0197] To a 0°C solution of 6-bromo-2,4-dihydro-1H-3,1-benzoxazin-2-one (2 g, 8.77 mmol) in DMF (20 mL) was added sodium hydroxide (526.17 mg, 13.16 mmol, 60% purity), followed by stirring at 0°C for 0.5 hours. A solution of iodomethane (1.87 g, 13.16 mmol) in DMF (5 mL) was then added dropwise, followed by stirring at 0°C for 1 hour. Water was added and the mixture was extracted with EtOAc (50 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried to give 6-bromo-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one (2 g, crude) as a colorless oil.

[0198] MS m / z(ESI):241.9243.9[M+1]

[0199] Step 2

[0200] 6-Bromo-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one (600 mg, 2.48 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (755.30 mg, 2.97 mmol), potassium acetate (729.78 mg, 7.44 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex ( A mixture of 1,4-dioxane (10 mL) and 1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one (700 mg, yield: 97.7%) was obtained by nitrogen replacement three times, followed by stirring at 90°C for 16 hours under nitrogen protection, followed by spin drying and column chromatography (PE / EA=2:1).

[0201] MS m / z(ESI):290.2[M+1]

[0202] Intermediate 5

[0203] first step

[0204] 6-Bromo-1-(methyl-d3)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one

[0205] Under ice bath, 6-bromo-1,4-dihydro-3,1-benzoxazin-2-one (10 g, 43.85 mmol) was dissolved in N,N-dimethylformamide (30 mL), and then sodium hydroxide (2.63 g, 65.78 mmol, 60%) was added in batches. The mixture was stirred under ice bath for 30 minutes, and then deuterated iodomethane (12.72 g, 87.70 mmol) was added dropwise. The mixture was stirred under ice bath for one hour. LCMS indicated that the reaction was complete. The reaction solution was then slowly added to ice water (300 mL) to quench the mixture, and then extracted with ethyl acetate (150 mL×3). The organic phases were combined, washed with saturated brine (100 mL×4), dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was directly used in the next step (9.0 g, yield: 83.7%).

[0206] MS m / z(ESI): 245.1, 247.1[M+1].

[0207] Step 2

[0208] 1-(Methyl-d3)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one

[0209] At room temperature, 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan-2-yl (12.23 g, 48.15 mmol), 6-bromo-1-(methyl-d3)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one (5.9 g, 24.07 mmol), potassium acetate (7.09 g, 72.22 mmol) and Pd(dppf)Cl2.CH2Cl2 were added. The product was dissolved in 1′4-dioxane (100 mL), nitrogen was replaced, heated to 90° C., reacted for 14 hours, cooled to room temperature, and LCMS indicated that the reaction was complete. The dioxane was then dried, and the residue was dissolved in ethyl acetate (200 mL). The organic phase was then washed with saturated brine (100 mL×3), dried over anhydrous sodium sulfate, filtered, and dried. The residue was separated by Flash column chromatography (PE:EA=10:1-4:1) to obtain the target compound (6.0 g, yield: 85%).

[0210] MS m / z(ESI):293.1[M+1].

[0211] Intermediate 6

[0212] first step

[0213] 6-Bromo-3H-1,3-benzothiazol-2-one (5 g, 21.73 mmol), iodomethane (6.17 g, 43.46 mmol), and DMF (50 mL) were added to a 100 mL flask. Cesium carbonate (14.16 g, 43.46 mmol) was added at room temperature, and the reaction mixture was allowed to react at 40°C for 3 h. The reaction mixture was added to ice water (100 mL) and extracted with EA (100 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 6-bromo-3-methyl-1,3-benzothiazol-2-one (5 g, yield: 94.25%).

[0214] MS m / z(ESI):243.9245.9[M+1]

[0215] Step 2

[0216] 6-Bromo-3-methyl-1,3-benzothiazol-2-one (5 g, 20.48 mmol), potassium acetate (4.02 g, 40.97 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (1.66 g, 2.05 mmol), bis(pinacolato)diboron (7.80 g, 30.72 mmol), and 1,4-dioxane (100 mL) were added to a 250 mL flask. The reaction mixture was then incubated at 90°C under nitrogen for 3 h. LCMS indicated the reaction was complete. The reaction solution was filtered, concentrated, and purified by column chromatography using PE / EA (3 / 1) to afford 3-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-benzothiazol-2-one (5 g, 83.8% yield).

[0217] MS m / z(ESI):292.1[M+1]

[0218] Intermediate 7

[0219] first step

[0220] 6-Bromo-3H-1,3-benzothiazol-2-one (30 g, 130.39 mmol), iodomethane-d3 (37.80 g, 260.78 mmol), and DMF (500 mL) were added to a 1000 mL flask. Cesium carbonate (84.97 g, 260.78 mmol) was added at 25°C, and the reaction solution was reacted at 40°C for 1 h. The reaction solution was added to ice water (500 mL) and extracted with EA (500 mL*2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 6-bromo-3-(methyl-d3)benzo[d]thiazol-2(3H)-one (30 g, yield: 93.10%).

[0221] MS m / z(ESI):246.9248.9[M+1]

[0222] Step 2

[0223] 6-Bromo-3-(methyl-d3)benzo[d]thiazol-2(3H)-one (32 g, 129.49 mmol), potassium acetate (24.12 g, 258.98 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (10.50 g, 12.95 mmol), bispinacol diboron (49.32 g, 194.23 mmol) and 1,4-dioxane (500 mL) were added to a 1000 mL flask, and the reaction liquid was protected with nitrogen at 90°C, and then reacted for 3 hours. LCMS showed that the reaction was complete. The reaction solution was filtered and concentrated, and then column purified with PE / EA = 3 / 1 to give 3-(methyl-d3)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2(3H)-one (30 g, yield: 78.8%).

[0224] MS m / z(ESI):295.1[M+1]

[0225] Intermediate 8

[0226] Using 6-bromo-1-methyl-1H-quinolin-2-one as starting material, the target intermediate was synthesized by referring to the second step of intermediate 2.

[0227] MS m / z(ESI):286.2[M+H].

[0228] Intermediate 9

[0229] Using 6-bromo-1-methyl-1H-quinolin-2-one as starting material, the target intermediate was synthesized by referring to the second step of intermediate 2.

[0230] MS m / z(ESI):289.2[M+H].

[0231] Example 1

[0232] first step

[0233] 4-Bromo-7,7-dimethoxy-6,7-dihydro-5H-cyclopenta[c]pyridin-6-ol

[0234] Potassium hydroxide (5.29 g, 94.32 mmol) was dissolved in methanol (50 mL). 4-Bromo-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one was added under nitrogen protection while cooling in an ice-water bath. The mixture was stirred at 0°C for 5 minutes. Iodobenzene acetate (6.08 g, 18.86 mmol) was then added. The mixture was stirred at 18°C ​​for 4 hours. The reaction solution was evaporated to dryness at low temperature. The crude product was quenched by adding saturated brine (100 mL) and extracted with ethyl acetate (50 mL × 3). The mixture was separated, and the organic phases were combined and washed with saturated brine (100 mL × 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluted with dichloromethane:methanol=100:0 to 95:5) to give the target product 4-bromo-7,7-dimethoxy-6,7-dihydro-5H-cyclopenta[c]pyridin-6-ol (1.5 g, brown oil) in a yield of 58.02%.

[0235] MS m / z(ESI): 274.0, 276.0[M+1].

[0236] Step 2

[0237] 4-Bromo-7,7-dimethoxy-7H-cyclopenta[c]pyridine

[0238] Dissolve 4-bromo-7,7-dimethoxy-6,7-dihydro-5H-cyclopenta[c]pyridin-6-ol (1.5 g, 5.47 mmol) and triethylamine (2.77 g, 27.36 mmol, 3.82 mL) in dichloromethane (60 mL). Add trifluoroacetic anhydride (2.30 g, 10.94 mmol, 1.52 mL) under nitrogen protection while cooling in an ice-water bath. Stir the mixture at 20°C for 12 hours. Quench the reaction by adding saturated aqueous sodium bicarbonate (150 mL). Separate the organic phase, wash with saturated brine (50 mL x 2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue was purified by flash silica gel chromatography (eluted with petroleum ether:ethyl acetate = 100:0 to 80:20) to give the target product, 4-bromo-7,7-dimethoxy-7H-cyclopenta[c]pyridine (1.3 g), in a yield of 92.76%.

[0239] MS m / z(ESI): 256.0, 258.0[M+1].

[0240] Step 3

[0241] 4-Bromo-6,6-dimethoxy-4b,5,5a,6-tetrahydrocyclopropeno[3,4]cyclopenta[1,2-c]pyridine

[0242] Trimethylsulfoxide iodide (3.35 g, 15.23 mmol) was dissolved in dimethylsulfoxide (20 mL), and sodium hydroxide (609.09 mg, 15.23 mmol, 60% w / w) was added under nitrogen. The mixture was stirred at 18°C ​​for 3 hours. 4-Bromo-7,7-dimethoxy-7H-cyclopenta[c]pyridine (1.30 g, 5.08 mmol) was added under nitrogen. The mixture was stirred at 18°C ​​for 12 hours. The reaction solution was quenched with saturated brine (130 mL) and extracted with ethyl acetate (50 mL × 2). The organic phase was separated, washed with saturated brine (50 mL × 5), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude 4-bromo-6,6-dimethoxy-4b,5,5a,6-tetrahydrocyclopropeno[3,4]cyclopenta[1,2-c]pyridine (1.1 g). The crude product was used directly in the next step.

[0243] MS m / z(ESI): 270.0, 272.0[M+1].

[0244] Step 4

[0245] 4-Bromo-5,5a-dihydrocyclopropeno[3,4]cyclopenta[1,2-c]pyridin-6(4bH)-one

[0246] Dissolve 4-bromo-6,6-dimethoxy-4b,5,5a,6-tetrahydrocyclopropeno[3,4]cyclopenta[1,2-c]pyridine (1.1 g, 4.07 mmol) in acetone (30 mL). Add p-toluenesulfonic acid monohydrate (774.61 mg, 4.07 mmol) under nitrogen. Stir the mixture at 18°C ​​for 2 hours. Evaporate the mixture to dryness at low temperature, quench the reaction with saturated brine (50 mL), and extract with dichloromethane (50 mL x 2). Combine the organic phases, wash with saturated brine (50 mL x 2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue was purified by flash silica gel chromatography (eluted with petroleum ether:ethyl acetate = 100:0 to 75:25) to give the target product, 4-bromo-5,5a-dihydrocyclopropeno[3,4]cyclopenta[1,2-c]pyridin-6(4bH)-one (0.55 g, light brown solid) in a yield of 60.28%.

[0247] MS m / z(ESI): 224.0, 226.0[M+1].

[0248] Step 5

[0249] 4-Bromo-4b,5,5a,6-tetrahydrocyclopropeno[3,4]cyclopenta[1,2-c]pyridin-6-amine

[0250] 4-Bromo-5,5a-dihydrocyclopropeno[3,4]cyclopenta[1,2-c]pyridin-6(4bH)-one (0.55 g, 2.45 mmol) was dissolved in a 2M ammonia-methanol solution (20 mL). Tetraisopropyl titanium oxide (2.16 g, 4.91 mmol) was added under nitrogen. The mixture was stirred at 60°C for 3 hours. The reaction solution was cooled to room temperature, and sodium borohydride (185.74 mg, 4.91 mmol) was added. The mixture was stirred at 20°C for 24 hours. The reaction solution was evaporated to dryness, and the crude product was dissolved in dichloromethane (60 mL), washed with saturated brine (30 mL x 2), and the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude 4-bromo-4b,5,5a,6-tetrahydrocyclopropeno[3,4]cyclopenta[1,2-c]pyridin-6-amine (0.44 g). The crude product was used directly in the next step.

[0251] MS m / z(ESI): 225.0, 227.0[M+1].

[0252] Step 6

[0253] N-(4-Bromo-4b,5,5a,6-tetrahydrocyclopropeno[3,4]cyclopenta[1,2-c]pyridin-6-yl)propanamide

[0254] Method 1: Synthesize N-(4-bromo-4b,5,5a,6-tetrahydrocyclopropeno[3,4]cyclopenta[1,2-c]pyridin-6-yl)propionamide using 4-bromo-4b,5,5a,6-tetrahydrocyclopropeno[3,4]cyclopenta[1,2-c]pyridin-6-amine and propionyl chloride. See WO2013041591 Intermediate B-5 step D.

[0255] Method 2: Dissolve 4-bromo-4b,5,5a,6-tetrahydrocyclopropeno[3,4]cyclopenta[1,2-c]pyridin-6-amine (10 g, 44.43 mmol) and triethylamine (13.49 g, 133.28 mmol, 18.59 mL) in DCM (150 mL). Add propionyl chloride (4.93 g, 53.31 mmol, 4.66 mL) under nitrogen and ice-water cooling. Stir the mixture at 0°C for 0.5 h. Quench the reaction by adding saturated brine (150 mL) and extract with dichloromethane (50 mL x 3). Combine the organic phases, wash with saturated brine (150 mL x 2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue was purified by flash silica gel chromatography (eluted with petroleum ether:ethyl acetate = 100:0 to 0:100) to give the desired product (7.5 g, yield: 60.04%).

[0256] MS m / z(ESI): 281.0, 283.0[M+1].

[0257] Step 7

[0258] Method 1: N-(4-(1-methyl-2-carbonyl-1,2,3,4-tetrahydroquinolin-6-yl)-4b,5,5a,6-tetrahydrocyclopropeno[3,4]cyclopenta[1,2-c]pyridin-6-yl)propanamide was synthesized using N-(4-bromo-4b,5,5a,6-tetrahydrocyclopropeno[3,4]cyclopenta[1,2-c]pyridin-6-yl)propanamide and 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one as raw materials. This method can be found in Intermediate A-2 step A of WO2013037779.

[0259] Method 2: N-(4-Bromo-4b,5,5a,6-tetrahydrocyclopropeno[3,4]cyclopenta[1,2-c]pyridin-6-yl)propanamide (74 mg, 263.21 μmol), 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one (75.58 mg, 263.21 μmol), and sodium carbonate (83.69 mg, 789.62 μmol) were dissolved in ethanol (10 mL) and water (2 mL). Tetrakistriphenylphosphine palladium (30.42 mg, 26.32 μmol) was added under nitrogen. The mixture was stirred at 90°C for 5 hours. The reaction solution was evaporated to dryness, and saturated brine (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 2). The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. The crude product was separated by preparative high performance liquid chromatography to obtain the product (20 mg, yield: 20.18%).

[0260] MS m / z(ESI):362.2[M+1].

[0261] The sample was chirally separated to obtain products P1 and P2.

[0262] Product P1 was chirally resolved under the following conditions to obtain 1-P1A and 1-P1B

[0263] Product P2 was chirally resolved under the following conditions to obtain 1-P2A and 1-P2B

[0264] The LCMS and HNMR of sample 1-2B are as follows:

[0265] 1H NMR (400MHz, CDCl3) δ8.48 (s, 1H), 8.40 (s, 1H), 7.50 (dd, J=8.4, 2.0Hz, 1H), 7.44-7.34 (m, 1H), 7.11 (d, J=8.4Hz, 1H), 6.04-5.88 (m, 1 H), 5.77-5.58 (m, 1H), 3.41 (s, 3H), 3.00 (t, J=7.4Hz, 2H), 2.79-2.64 (m, 2H), 2.60-2.48 (m, 1H), 2.40-2.21 (m, 3H), 1.37-1.15 (m, 5H).

[0266] MS m / z(ESI):362.2[M+1].

[0267] Example 2

[0268] N-((6R)-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)-4b,5,5a,6-tetrahydrocyclopropyl[3,4]cyclopentadienyl[1,2-c]pyridin-6-yl)propanamide

[0269] Using N-((6R)-4-bromo-4b,5,5a,6-tetrahydrocyclopropyl[3,4]cyclopentadienyl[1,2-c]pyridin-6-yl)propionamide and 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2(3H)-one as starting materials, with reference to Step 7 of Example 1, the product N-((6R)-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)-4b,5,5a,6-tetrahydrocyclopropyl[3,4]cyclopentadienyl[1,2-c]pyridin-6-yl)propionamide was obtained. This product was subjected to a first chiral resolution to give products P1, P2, and P3 under the following resolution conditions.

[0270] P1 was subjected to a second chiral resolution to obtain products P1A and P1B. The resolution conditions were as follows.

[0271] The structure, MS and HNMR of 2-2 are as follows:

[0272] MS m / z(ESI):366.1[M+1].

[0273] 1H NMR (400MHz, MeOD) δ8.41 (s, 1H), 8.26 (s, 1H), 7.91-7.80 (m, 1H), 7.75-7.60 (m, 1H), 7.45-7.35 (m, 1H), 7.29-7.06 (m, 1H), 5.84 (d, J=6.6H z, 1H), 3.52 (s, 3H), 2.63-2.49 (m, 1H), 2.38-2.29 (m, 2H), 2.29-2.20 (m, 1H), 1.21 (t, J=7.7Hz, 3H), 0.95-0.85 (m, 1H), 0.69-0.60 (m, 1H).

[0274] Example compounds 3-10 can be prepared by referring to Example 1 or 2.

[0275] Example 3-1

[0276] Step 1: N-(4-bromo-4b,5,5a,6-tetrahydrocyclopropeno[3,4]cyclopenta[1,2-c]pyridin-6-yl)propanamide

[0277] Dissolve 4-bromo-4b,5,5a,6-tetrahydrocyclopropeno[3,4]cyclopenta[1,2-c]pyridin-6-amine (10 g, 44.43 mmol) and triethylamine (13.49 g, 133.28 mmol, 18.59 mL) in dichloromethane (150 mL). Cool under an ice-water bath and nitrogen, then add propionyl chloride (4.93 g, 53.31 mmol, 4.66 mL). Stir the mixture at 0°C for 0.5 hours. Quench the reaction by adding saturated brine (150 mL) and extract with dichloromethane (50 mL x 3). Combine the organic phases, wash with saturated brine (150 mL x 2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue was purified by flash silica gel chromatography (eluted with petroleum ether:ethyl acetate = 100:0 to 0:100) to give the desired product (7.5 g, yield: 60.04%).

[0278] MS m / z(ESI): 281.0, 283.0[M+1].

[0279] Step 2: N-((4bS,5aR,6R)-4-bromo-4b,5,5a,6-tetrahydrocyclopropen[3,4]cyclopenta[1,2-c]pyridin-6-yl)propanamide

[0280] After chiral separation, two components P1 and P2 were obtained, with P2 being the target compound. The specific conditions are as follows:

[0281] MS m / z(ESI): 281.0, 283.0[M+1].

[0282] Step 3: N-((4bS,5aR,6R)-4-(1-(methyl-d3)-2-carbonyl-1,2,3,4-tetrahydroquinolin-6-yl)-4b,5,5a,6-tetrahydrocyclopropen[3,4]cyclopenta[1,2-c]pyridin-6-yl)propanamide

[0283] N-((4bS,5aR,6R)-4-bromo-4b,5,5a,6-tetrahydrocyclopropeno[3,4]cyclopenta[1,2-c]pyridin-6-yl)propanamide (0.5 g, 1.78 mmol) and 1-(methyl-d3)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one (567.67 mg, 1.96 mmol) were dissolved in ethanol (40 mL) and water (8 mL). Tetrakistriphenylphosphine palladium (102.75 mg, 88.92 μmol) and sodium carbonate (565.48 mg, 5.34 mmol) were added under nitrogen. The mixture was stirred at 90°C for 6 hours. The reaction mixture was rotary evaporated to remove most of the solvent, and saturated brine (100 mL) was added. The aqueous phase was extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (dichloromethane:methanol = 100:0 to 95:5) to obtain a crude product. The crude product was separated by preparative HPLC to obtain the product, which was then further separated by normal chiral preparative separation to obtain the desired product (0.4 g, yield: 61.71%).

[0284] 1 H NMR (400MHz, DMSO) δ8.44 (s, 1H), 8.22 (s, 1H), 8.17 (d, J=8.0Hz, 1H), 7.61-7.49 (m, 2H), 7.24 (d, J=8.3Hz, 1H), 5.77-5.68 (m, 1H), 2.96 (t, J=7.4 Hz, 2H), 2.65-2.56 (m, 2H), 2.49-2.45 (m, 1H), 2.25-2.16 (m, 2H), 2.16-2 .04(m, 1H), 1.20-1.11(m, 1H), 1.08(t, J=7.6Hz, 3H), 0.64-0.55(m, 1H).

[0285] MS m / z(ESI):365.2[M+1].

[0286] Examples 4-1, 5-1, 6-1, 7-1, 8-1, 9-1 and 10-1 can be prepared with reference to Example 3-1.

[0287] Example 11

[0288] first step

[0289] 3,5-Dibromopyridine (2 g, 8.44 mmol) and tert-butyl N-(4-piperidinyl)carbamate (1.69 g, 8.44 mmol) were dissolved in 1,4-dioxane (50 mL). t-BuONa (1.22 g, 12.66 mmol), Pd2(dba)3 (773.11 mg, 844.27 μmol), and Xantphos (977.01 mg, 1.69 mmol) were added sequentially. The reaction system was purged with nitrogen several times and then stirred in an oil bath at 90°C for 16 hours. After completion of the reaction, the mixture was cooled to room temperature and quenched with water (20 mL). The mixture was extracted with ethyl acetate (50 mL x 2), washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (Petroleum ether: Ethyl acetate = 3:1, UV = 254 nm) to give tert-butyl N-[1-(5-bromo-3-pyridinyl)-4-piperidinyl]carbamate (1.8 g, 5.05 mmol, 59.85% yield) as a pale yellow solid.

[0290] MS m / z(ESI): 356.1, 358.1[M+H] +

[0291] Step 2

[0292] Tert-butyl N-[1-(5-bromo-3-pyridyl)-4-piperidinyl]carbamate (400 mg, 1.12 mmol) was dissolved in DMF (10 mL) and NaH (89.81 mg, 2.25 mmol, 60% purity) was added in an ice-water bath. After stirring in an ice-water bath for 0.5 h, CD3I (325.51 mg, 2.25 mmol) was added. The reaction system was stirred at room temperature (20°C) for 3.5 h. After completion of the reaction, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL x 2), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (Petroleum ether:Ethyl acetate=3:1, UV=254 nm) to give the target product, tert-butyl N-[1-(5-bromo-3-pyridinyl)-4-piperidinyl]N-(deuteratedmethyl)carbamate (330 mg, 884.00 μmol, 78.73% yield).

[0293] MS m / z(ESI): 373.1, 375.1[M+H] +

[0294] Step 3

[0295] Tert-butyl N-[1-(5-bromo-3-pyridyl)-4-piperidinyl]-N-(deuterated methyl)carbamate (330 mg, 884.00 μmol) was dissolved in DCM (10 mL), and TFA (2.02 g, 17.68 mmol, 1.31 mL) was added. The reaction system was stirred at room temperature (20°C) for 4 hours. After completion, the reaction was quenched with saturated sodium bicarbonate solution (10 mL), extracted with dichloromethane (20 mL x 2), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude 1-(5-bromo-3-pyridyl)-N-deuterated methylpiperidin-4-amine (240 mg, crude). The crude product was used directly in the next reaction.

[0296] MS m / z(ESI): 273.1, 275.1[M+H] +

[0297] Step 4

[0298] 1-(5-Bromo-3-pyridyl)-N-deuterated methylpiperidin-4-amine (300 mg, 1.10 mmol) and 1-methylpyrazole-4-carboxylic acid (166.19 mg, 1.32 mmol) were dissolved in DMF (20 mL). Triethylamine (333.37 mg, 3.29 mmol, 459.50 μL) and HATU (828.60 mg, 2.20 mmol) were added. The reaction system was stirred at room temperature (20°C) for 4 hours. After completion of the reaction, water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL x 2). The mixture was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (Petroleum ether:Ethyl acetate=3:1, UV=254 nm) to give the target product, N-[1-(5-bromo-3-pyridinyl)-4-piperidinyl]-1-methyl-N-deuteromethylpyrazole-4-carboxamide (330 mg, 865.49 μmol, 78.81% yield).

[0299] MS m / z(ESI): 381.1, 383.1[M+H] +

[0300] Step 5

[0301] 1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one (83.41 mg, 288.50 μmol) and N-[1-(5-bromo-3-pyridyl)-4-piperidinyl]-1-methyl-N-deuterated methylpyrazole-4-carboxamide (100 mg, 262.27 μmol) were dissolved in a mixed solvent of water (5 mL) and ethanol (15 mL). Pd(PPh3)4 (30.31 mg, 26.23 μmol) and sodium carbonate (83.39 mg, 786.81 μmol) were added sequentially. The reaction system was purged with nitrogen several times and then stirred in an oil bath at 100°C for 6 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with water (10 mL), extracted with ethyl acetate (20 mL x 2), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude pale yellow solid (120 mg). The crude product was purified by prep-HPLC to give 1-methyl-N-(methyl-d3)N-(1-(5-(1-methyl-2-carbonyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)pyridin-3-yl)piperidin-4-yl)-1H-pyrazole-4-carboxamide (11.7 mg, 25.24 μmol, 9.75% yield) as a white solid.

[0302] MS m / z(ESI):464.2[M+H] +

[0303] Example 12

[0304] 1-Methyl-6-(6-(2-carbonylazetidin-1-yl)-4b,5,5a,6-tetrahydrocyclopropeno[3,4]cyclopenta[1,2-c]pyridin-4-yl)-3,4-dihydroquinolin-2(1H)-one

[0305] first step

[0306] At room temperature, 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one (0.34 g, 1.2 mmol), 4-bromo-4b,5,5a,6-tetrahydrocyclopropen[3,4]cyclopentadien[1,2-c]pyridin-6-amine (0.22 g, 1.0 mmol), sodium carbonate (0.32 g, 3 mmol) and tetrakistriphenylphosphine palladium (0.06 g, 0.05 mmol) were dissolved in ethanol ( The mixture was stirred for 2 hours at room temperature for 3 hours. The mixture was stirred for 2 hours at room temperature for 3 hours. The mixture was stirred for 3 hours at room temperature for 3 hours. The mixture was stirred for 4 hours. The mixture was stirred for 5 minutes. The mixture was stirred for 3 hours. The mixture was stirred for 5 minutes. The mixture was stirred for 3 hours.

[0307] MS m / z(ESI):306.2[M+1].

[0308] Step 2

[0309] Under ice bath, 6-(6-amino-4b,5,5a,6-tetrahydrocyclopropen[3,4]cyclopentadien[1,2-c]pyridin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (0.122 g, 0.4 mmol) was dissolved in dichloromethane (5 mL), and then triethylamine (0.12 g, 1.2 mmol) and 3-chloropropionyl chloride (0.06 g, 0.5 mmol) were added in sequence. The mixture was stirred at room temperature for 1 hour. LCMS indicated that the reaction When the reaction was complete, the reaction solution was diluted with dichloromethane (20 mL), then washed with saturated brine (15 mL × 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to give the target product 3-chloro-N-(4-(1-methyl-2-carbonyl-1,2,3,4-tetrahydroquinolin-6-yl)-4b,5,5a,6-tetrahydrocyclopropen-[3,4]cyclopenta-[1,2-c]pyridin-6-yl)propanamide, which was directly used in the next step (0.14 g, yield: 90%).

[0310] MS m / z(ESI):396.2[M+1].

[0311] Step 3

[0312] At room temperature, 3-chloro-N-(4-(1-methyl-2-carbonyl-1,2,3,4-tetrahydroquinolin-6-yl)-4b,5,5a,6-tetrahydrocyclopropen[3,4]cyclopenta[1,2-c]pyridin-6-yl)propanamide (0.14 g, 0.36 mmol) was dissolved in acetonitrile (5 mL), and then cesium carbonate (0.23 g, 0.72 mmol) was added, nitrogen was replaced, and the mixture was heated to 90 ° C. and reacted for 5 hours. LCMS indicated that the reaction was complete, and the mixture was cooled to room temperature. , spin-dried, the residue was dissolved in ethyl acetate (20 mL), then washed with saturated brine (15 mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified by reverse phase preparative chromatography and lyophilized to give 1-methyl-6-(6-(2-carbonylazetidin-1-yl)-4b,5,5a,6-tetrahydrocyclopropene[3,4]cyclopentadien[1,2-c]pyridin-4-yl)-3,4-dihydroquinolin-2(1H)-one (0.026 g, yield: 20%).

[0313] MS m / z(ESI):360.2[M+1].

[0314] Compound 12 was subjected to chiral resolution to obtain the following single-configuration compound:

[0315] Referring to Example 12, compound 13-21 was prepared.

[0316] Example 22

[0317] first step

[0318] 1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4H-3,1-benzoxazin-2-one (305.56 mg, 1.06 mmol), (R)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine (200 mg, 880.67 μmol), and sodium carbonate (280.03 mg, 2.64 mmol) were dissolved in ethanol (8 mL) and water (2 mL). After nitrogen displacement, tetrakistriphenylphosphine palladium (50.88 mg, 44.03 μmol) was added, and nitrogen was replaced again. The reaction solution was heated to 90°C for 5 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol = 4:1) to give the target compound (R)-6-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one (200 mg, 646.49 μmol, 73.41% yield).

[0319] MS m / z(ESI):310.1[M+1].

[0320] Step 2

[0321] A mixture of (R)-6-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one (200 mg, 646.49 μmol), trifluoroacetic anhydride (407.35 mg, 1.94 mmol, 273.39 μL), and triethylamine (196.26 mg, 1.94 mmol, 270.51 μL) in dichloromethane (5 mL) was heated to 40°C for 5 hours. The reaction solution was diluted with water (20 mL) and extracted with dichloromethane (50 mL). The organic phase was collected, dried, concentrated, and purified by preparative high performance liquid chromatography to give (R)-2,2,2-trifluoro-N-(4-(1-methyl-2-carbonyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)acetamide (100 mg, 246.69 μmol, 38.16% yield).

[0322] MS m / z(ESI):406.1[M+1].

[0323] 1H NMR (400MHz, DMSO) δ9.95 (d, J=8.0Hz, 1H), 8.33 (s, 1H), 8.26 (s, 1H), 7.41-7.35 (m, 1H), 7.33-7.28 (m, 1H), 7.23-7.17 (m, 1H) ), 5.31(s, 2H), 5.22-5.15(m, 1H), 3.33(s, 3H), 2.68-2.57(m, 2H), 2.03-1.91(m, 1H), 1.90-1.77(m, 2H), 1.76-1.66(m, 1H).

[0324] Example 23

[0325] first step

[0326] 2,3-Dihydro-4H-pyrano[3,2-c]pyridin-4-one (1 g, 6.70 mmol) was dissolved in DMF (20 mL), and NBS (1.31 g, 7.38 mmol) was added under nitrogen. The mixture was stirred at 70°C for 3 hours. After completion of the reaction, saturated aqueous sodium bicarbonate solution (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain the title product, 8-bromo-2,3-dihydro-4H-pyrano[3,2-c]pyridin-4-one (400 mg, yellow solid), in a yield of 26.16%.

[0327] MS m / z(ESI): 228.0, 230.0[M+H].

[0328] Step 2

[0329] In a 50 mL reaction flask, 8-bromo-2,3-dihydro-4H-pyrano[3,2-c]pyridin-4-one (200 mg, 877.03 μmol) was dissolved in methanol (5 mL), followed by the addition of sodium borohydride (33.18 mg, 877.03 μmol). The reaction mixture was stirred at 25°C for 10 minutes. The reaction was stopped and quenched with water (5 mL). The mixture was extracted with ethyl acetate (5 mL x 2). The combined organic phases were washed with saturated sodium chloride (5 mL), dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel column chromatography using dichloromethane and methanol as eluents to afford the title product, 8-bromo-3,4-dihydro-2H-pyrano[3,2-c]pyridin-4-ol (200 mg, yellow solid), in a yield of 99.12%.

[0330] MS m / z(ESI): 230.0, 232.0[M+H].

[0331] Step 3

[0332] In a 50 mL reaction flask, 8-bromo-3,4-dihydro-2H-pyrano[3,2-c]pyridine-4-ol (200 mg, 869.34 μmol) was dissolved in dichloromethane (5 mL). Thionyl chloride (517.13 mg, 4.35 mmol, 315.71 μL) was then slowly added dropwise. The reaction mixture was stirred at 50°C for 10 minutes. The reaction was stopped and the reaction mixture was concentrated to obtain the title product, 8-bromo-4-chloro-3,4-dihydro-2H-pyrano[3,2-c]pyridine (210 mg, yellow solid), in a yield of 97.21%.

[0333] MS m / z(ESI): 247.9, 249.9[M+H].

[0334] Step 4

[0335] 8-Bromo-4-chloro-3,4-dihydro-2H-pyrano[3,2-c]pyridine (200 mg, 804.82 μmol) was dissolved in an aqueous ammonia isopropanol solution (10 mL). The mixture was stirred in a sealed microwave oven at 100°C for 3 hours. The reaction solution was concentrated to give the title product, 8-bromo-3,4-dihydro-2H-pyrano[3,2-c]pyridin-4-amine (180 mg, yellow solid), in a yield of 97.63%.

[0336] MS m / z(ESI): 229.0, 231.0[M+H].

[0337] Step 5

[0338] In a 50 mL reaction flask, 8-bromo-3,4-dihydro-2H-pyrano[3,2-c]pyridin-4-amine (100 mg, 436.54 μmol) was dissolved in dichloromethane (5 mL). DIEA (282.10 mg, 2.18 mmol, 380.19 μL) and propionyl chloride (40.39 mg, 436.54 μmol) were slowly added. The reaction solution was stirred at 25 ° C for 10 minutes. The reaction was stopped, water (5 mL) was added to quench the reaction, extracted with dichloromethane (5 mL × 2), the combined organic phases were washed with saturated sodium chloride (5 mL), dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel column chromatography with an eluent system of dichloromethane and methanol to give the title product N-(8-bromo-3,4-dihydro-2H-pyrano[3,2-c]pyridin-4-yl)propionamide (110 mg, yellow solid), yield: 88.37%.

[0339] MS m / z(ESI): 285.0, 287.0[M+H].

[0340] Step 6

[0341] In a 50 mL reaction bottle, N-(8-bromo-3,4-dihydro-2H-pyrano[3,2-c]pyridin-4-yl)propionamide (103.65 mg, 363.49 μmol), 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4H-3,1-benzoxazin-2-one (105.10 mg, 363.49 μmol), tetrakis(triphenylphosphine)palladium (42.00 mg, 36.35 μmol), and Na2CO3 (154.49 mg, 1.46 mmol) were dissolved in ethanol (5 mL) and water (5 mL), and the reaction liquid was reacted at 90 ° C for 3 h under nitrogen protection. The reaction was stopped and quenched by adding water (5 mL). The mixture was extracted with dichloromethane (5 mL × 2). The combined organic phases were washed with saturated sodium chloride (5 mL), dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel column chromatography with an eluent system of dichloromethane and methanol to give the title product N-(8-(1-methyl-2-carbonyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-3,4-dihydro-2H-pyrano[3,2-c]pyridin-4-yl)propanamide (90 mg, white solid) in a yield of 67.39%.

[0342] MS m / z(ESI):368.1[M+H].

[0343] Step 7

[0344] N-(8-(1-methyl-2-carbonyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-3,4-dihydro-2H-pyrano[3,2-c]pyridin-4-yl)propionamide was subjected to chiral separation to obtain two components, P1 and P2. P2 is the target compound (R)-N-(8-(1-methyl-2-carbonyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-3,4-dihydro-2H-pyrano[3,2-c]pyridin-4-yl)propionamide. The specific conditions are as follows:

[0345] The LCMS and HNMR of sample P2 are as follows

[0346] MS m / z(ESI):368.1[M+H].

[0347] 1H NMR (400MHz, MeOD) δ8.28-8.23 (m, 2H), 7.59-7.52 (m, 1H), 7.43 (d, J=2.0Hz, 1H), 7.17 (d, J=8.5Hz, 1H), 5 .30(s, 2H), 5.25-5.17(m, 1H), 4.47-4.30(m, 2H), 3.40(s, 3H), 2.35-2.01(m, 4H), 1.18(t, J=7.6Hz, 3H).

[0348] Example 24

[0349] first step

[0350] Sodium hydroxide (638.72 mg, 15.97 mmol, 60% purity) was added portionwise to a solution of methyl 5-bromo-4-chloronicotinate (2 g, 7.98 mmol) and ethyl 2-hydroxyacetate (997.50 mg, 9.58 mmol, 906.82 μL) in N,N-dimethylformamide (40 mL) at 0°C. The mixture was allowed to warm to room temperature and allowed to react for 4 hours. The reaction mixture was poured into aqueous acetic acid (25 mL, 1 M), and the solid was filtered and dried. The filtrate was diluted with water and extracted with ethyl acetate (100 mL). The organic phase was collected, washed with saturated sodium chloride solution (100 mL), and concentrated. The concentrated organic phase and the filter cake were combined to obtain ethyl 7-bromo-3-carbonyl-2,3-dihydrofuro[3,2-c]pyridine-2-carboxylate (2 g, 6.99 mmol, 87.56% yield) as a light red solid, which was used directly in the next step.

[0351] MS m / z(ESI): 285.9, 287.9[M+1].

[0352] Step 2

[0353] Under a nitrogen atmosphere, dilute hydrochloric acid (6 M, 51.27 mL) and ethyl 7-bromo-3-carbonyl-2,3-dihydrofuro[3,2-c]pyridine-2-carboxylate (4.4 g, 15.38 mmol) were heated to 100°C for 8 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product, 7-bromofuro[3,2-c]pyridin-3(2H)-one (3 g, 14.02 mmol, 91.14% yield). This product was used directly in the next step.

[0354] MS m / z(ESI): 214.0, 216.0[M+1].

[0355] Step 3

[0356] Under nitrogen atmosphere, sodium acetate (613.26 mg, 7.48 mmol) was added to a solution of 7-bromofuro[3,2-c]pyridin-3(2H)-one (800 mg, 3.74 mmol) and hydroxylamine hydrochloride (649.40 mg, 9.35 mmol) in ethanol (20 mL). The mixture was heated to 50°C and stirred for 3 hours. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with water and dried. The filtrate was concentrated to remove ethanol and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filter cake and filtrate concentrate were combined to obtain 7-bromofuro[3,2-c]pyridin-3(2H)-one oxime (600 mg, 2.62 mmol, 70.08% yield), which was used directly in the next step.

[0357] MS m / z(ESI): 229.0, 231.0[M+1].

[0358] Step 4

[0359] Under nitrogen atmosphere, sodium borohydride (198.22 mg, 5.24 mmol) was dissolved in ethylene glycol dimethyl ether (8 mL), cooled to 0 ° C, and titanium tetrachloride (496.91 mg, 2.62 mmol, 287.90 μL) was slowly added dropwise. After 5 minutes, 7-bromofurano[3,2-c]pyridine-3(2H)-one oxime (300 mg, 1.31 mmol) suspended in ethylene glycol dimethyl ether (7 mL) was carefully added dropwise to the above mixture. Naturally warmed to room temperature and stirred for 8 hours. The reaction solution was carefully quenched with water (20 mL), extracted with ethyl acetate (60 mL), separated, and the aqueous phase was collected. The aqueous phase was washed with C 18 After purification on a reverse phase silica gel column, 7-bromo-2,3-dihydrofuro[3,2-c]pyridin-3-amine (70 mg, 325.51 μmol, 24.85% yield) was obtained.

[0360] MS m / z(ESI): 215.0, 217.0[M+1].

[0361] Step 5

[0362] Under a nitrogen atmosphere, propionyl chloride (15.06 mg, 162.76 μmol, 14.14 μL) was added to a solution of 7-bromo-2,3-dihydrofuro[3,2-c]pyridin-3-amine (70 mg, 325.51 μmol) and triethylamine (98.82 mg, 976.53 μmol, 136.20 μL) in dichloromethane (3 mL) at 25°C, and the reaction was stirred and maintained at temperature for 1 hour. The reaction solution was quenched with water (15 mL), extracted with dichloromethane (30 mL × 3), and the organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product N-(7-bromo-2,3-dihydrofuro[3,2-c]pyridin-3-yl)propionamide (60 mg, 221.31 μmol, 67.99% yield), which was directly used in the next step.

[0363] MS m / z(ESI): 271.0, 273.0[M+1].

[0364] Step 6

[0365] 1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one (76.79 mg, 265.57 μmol), N-(7-bromo-2,3-dihydrofuro[3,2-c]pyridin-3-yl)propionamide (60 mg, 221.31 μmol), and sodium carbonate (70.37 mg, 663.94 μmol) were dissolved in ethanol (2 mL) and water (0.5 mL). After nitrogen replacement, tetrakistriphenylphosphine palladium (12.79 mg, 11.07 μmol) was added, and nitrogen replacement was performed again. The reaction solution was heated to 90°C for 5 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol=5:1) to give the target compound N-(7-(1-methyl-2-carbonyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-2,3-dihydrofuro[3,2-c]pyridin-3-yl)propanamide (20 mg).

[0366] MS m / z(ESI):354.1[M+1].

[0367] Step 7

[0368] A sample of N-(7-(1-methyl-2-carbonyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-2,3-dihydrofuro[3,2-c]pyridin-3-yl)propanamide (20 mg) was chirally separated to give products P1 and P2.

[0369] The samples and HNMR are as follows:

[0370] 1 H NMR (400MHz, MeOD) δ8.54 (s, 1H), 8.39 (s, 1H), 7.84-7.73 (m, 1H), 7.70-7.61 (m, 1H), 7.21 (d, J=8.4Hz, 1H), 5.76-5. 64 (m, 1H), 5.32 (s, 2H), 4.94-4.92 (m, 1H), 4.57-4.50 (m, 1H), 3.41 (s, 3H), 2.29-2.18 (m, 2H), 1.15 (t, J=7.6Hz, 3H).

[0371] 1 H NMR (400MHz, MeOD) δ8.54 (s, 1H), 8.39 (s, 1H), 7.84-7.76 (m, 1H), 7.69-7.63 (m, 1H), 7.21 (d, J=8.4Hz, 1H), 5.72-5. 65 (m, 1H), 5.32 (s, 2H), 4.94-4.91 (m, 1H), 4.56-4.51 (m, 1H), 3.41 (s, 3H), 2.28-2.20 (m, 2H), 1.15 (t, J=7.6Hz, 3H).

[0372] Example 25

[0373] first step

[0374] At room temperature, (R)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine (0.65 g, 2.86 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trideuteriomethyl)-4H-3,1-benzoxazin-2-one (1 g, 3.42 mmol), sodium carbonate (910.07 mg, 8.59 mmol) and tetrakistriphenylphosphine palladium (165.43 mg, 143.11 μm) were added. The mixture was dissolved in ethanol (15 mL) and water (3 mL), the atmosphere was replaced with nitrogen, and the reaction was heated to 85°C for 14 hours. The mixture was cooled to room temperature. LCMS indicated that the reaction was complete. The mixture was spin-dried and the residue was separated by flash column chromatography (DCM:MeOH=95:5-80:20) to obtain the target compound as a brown oily substance (R)-6-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-(methyl-d3)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one.

[0375] (0.72 g, yield: 80.5%).

[0376] MS m / z(ESI):313.2[M+1].

[0377] Step 2

[0378] Under ice bath, (R)-6-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-(methyl-d3)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one (0.72 g, 2.30 mmol) was dissolved in dichloromethane (10 mL), and then triethylamine (699.69 mg, 6.91 mmol) and propionyl chloride (234.58 mg, 2.54 mmol) were added in sequence. The mixture was stirred at room temperature for 1 hour. LCMS indicated that the reaction was complete. When the reaction was complete, the reaction solution was diluted with dichloromethane (20 mL), then washed with saturated brine (15 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was separated by reverse phase preparative chromatography and freeze-dried to give the target product (R) N-(4-(1-(methyl-d3)-2-carbonyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide (0.41 g, yield: 48.3%).

[0379] MS m / z(ESI):369.2[M+1].

[0380] 1 H NMR (400MHz, DMSO-d6) δ8.33 (s, 1H), 8.30 (d, J = 8.0Hz, 1H), 8.21 (s, 1H), 7.38 (dd, J1 = 8.0Hz, J2 = 1.6Hz, 1H), 7.29 (d, J = 1.6Hz, 1H), 7 .18 (d, J=8.0Hz, 1H), 5.30 (s, 2H), 5.12-5.07 (m, 1H), 2.62-2.58 (m, 2H), 2.21-2.12 (m, 2H), 1.92-1.62 (m, 4H), 1.06 (d, J=7.6Hz, 3H).

[0381] Example 26

[0382] Using intermediate 8 as raw material, the target product N-((4bS,5aR,6R)-4-(1-methyl-2-carbonyl-1,2-dihydroquinolin-6-yl)-4b,5,5a,6-tetrahydrocyclopropen[3,4]cyclopenta[1,2-c]pyridin-6-yl)propanamide was synthesized with reference to Example 3-1.

[0383] MS m / z(ESI):360.2[M+1].

[0384] Example 27

[0385] Using intermediate 8 and acetyl chloride as raw materials, the target product N-((4bS,5aR,6R)-4-(1-methyl-2-carbonyl-1,2-dihydroquinolin-6-yl)-4b,5,5a,6-tetrahydrocyclopropeno[3,4]cyclopenta[1,2-c]pyridin-6-yl)acetamide was synthesized with reference to Example 3-1.

[0386] MS m / z(ESI):346.2[M+1].

[0387] Example 28

[0388] Using intermediate 8 as the starting material, the target product N-((4bS,5aR,6R)-4-(1-(methyl-d3)-2-carbonyl-1,2-dihydroquinolin-6-yl)-4b,5,5a,6-tetrahydrocyclopropeno[3,4]cyclopenta[1,2-c]pyridin-6-yl)propanamide was synthesized with reference to Example 3-1.

[0389] MS m / z(ESI):363.2[M+1].

[0390] Example 29

[0391] Using intermediate 8 and acetyl chloride as raw materials, the target product N-((4bS,5aR,6R)-4-(1-(methyl-d3)-2-carbonyl-1,2-dihydroquinolin-6-yl)-4b,5,5a,6-tetrahydrocyclopropen[3,4]cyclopenta[1,2-c]pyridin-6-yl)acetamide was synthesized with reference to Example 3-1.

[0392] MS m / z(ESI):349.2[M+1].

[0393] Example 30

[0394] Using intermediate 3 and acetyl chloride as raw materials, the target product N-((4bS,5aR,6R)-4-(1-(methyl-d3)-2-carbonyl-1,2,3,4-tetrahydroquinolin-6-yl)-4b,5,5a,6-tetrahydrocyclopropen[3,4]cyclopenta[1,2-c]pyridin-6-yl)acetamide was synthesized with reference to Example 3-1.

[0395] MS m / z(ESI):351.2[M+1].

[0396] Example 31

[0397] Using intermediate 3 and butyryl chloride as raw materials, the target product N-((4bS,5aR,6R)-4-(1-(methyl-d3)-2-carbonyl-1,2,3,4-tetrahydroquinolin-6-yl)-4b,5,5a,6-tetrahydrocyclopropen[3,4]cyclopentadien[1,2-c]pyridin-6-yl)butanamide was synthesized with reference to Example 3-1.

[0398] MS m / z(ESI):379.2[M+1].

[0399] Example 32

[0400] Using intermediate 3 and cyclopropanoyl chloride as raw materials, the target product N-((4bS,5aR,6R)-4-(1-(methyl-d3)-2-carbonyl-1,2,3,4-tetrahydroquinolin-6-yl)-4b,5,5a,6-tetrahydrocyclopropeno[3,4]cyclopenta[1,2-c]pyridin-6-yl)cyclopropanecarboxamide was synthesized with reference to Example 3-1.

[0401] MS m / z(ESI):377.2[M+1].

[0402] Biological test evaluation

[0403] The present invention is further described and explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[0404] Test Example 1

[0405] The G-402 cell line is used as a host cell to express (transiently or stably) enzymes of the human CYP11 family. Specifically, G-402 cell lines stably expressing human CYP11B1 and human CYP11B2 were established. It has been confirmed that the G-402 cell line expresses cofactors (cortical ferredoxin and cortical ferredoxin reductase) that are important for the activity of the CYP11 family, and (compared to H295R cells) the cell line itself does not have CYP11 family-related enzyme activity. Therefore, the G-402 cell line is very suitable as a host cell for ectopic expression of CYP11 family enzymes.

[0406] The G-402 cell line was originally derived from renal myoblastoma and can be obtained from ATCC (CRL-1440). The main components of the expression plasmid include the ORF of human CYP11B1 or human CYP11B2, a suitable promoter (CMV promoter), and a suitable resistance marker (neomycin). The expression plasmid is transfected into G-402 cells using standard techniques and then screened with specific antibiotics. The activity of the enzyme expressed by the screened monoclonal cells is evaluated using 11-deoxycorticosterone (a substrate for CYP11B2) and 11-deoxycortisol (a substrate for CYP11B1).

[0407] G-402 cells expressing the CYP11 plasmid established with the above protocol were cultured in McCoy's 5a modified medium (ATCC Catalog No. 30-2007) containing 10% FCS and 400 μg / ml G418 at 37°C in a 5% CO2 incubator. Enzyme assays were performed using DMEM / F12 medium containing 2.5% charcoal-stripped FBS and the appropriate concentration of substrate (1 μM 11-deoxycorticosterone or 1 μM 11-deoxycortisol). To measure enzyme activity, cells were plated in 96-well plates and incubated for 16 hours. The supernatant was then transferred and analyzed for the concentration of the expected product (aldosterone for CYP11B2 and cortisol for CYP11B1). The concentrations of these products were determined using CisBio's HTRF assay.

[0408] In cell enzyme experiments, the inhibitory effect of the test compound on the generated product can reflect its inhibitory effect on the enzyme. The dose-dependent inhibition of the compound on the enzyme activity is calculated by plotting the test compound concentration (x-axis) against the measured product level (y-axis). The raw data are then fitted to a 4-parameter sigmoid function (Morgan-Mercer-Flodin, MMF model) using the least squares method: y = (AB + Cx D ) / (B+x D )

[0409] Where A is the maximum y value and B is the EC determined using XLFit 50 , C is the minimum y value, and D is the slope value. The maximum value A corresponds to the amount of product detected in the absence of inhibitors, and C corresponds to the amount of product detected in G402 cells expressing the empty plasmid.

[0410] The EC of this patented compound 50 The values ​​were determined using the G-402 assay system described above. CYP11B2 enzyme activity was determined in the presence of 1 μM 11-deoxycorticosterone and variable amounts of inhibitors, and CYP11B1 enzyme activity was determined in the presence of 1 μM 11-deoxycortisol and variable amounts of inhibitors.

[0411] Note: hSF is the abbreviation of human selective factor, which refers to the selectivity of compound CYP11B2 for CYP11B1. The value of hSF is the CYP11B1 EC 50 and CYP11B2 EC 50 ratio.

[0412] It can be seen from the above data that the compound of the present invention has good CYP11B2 activity and, compared with the CYP11B1 enzyme, has higher selectivity, with a selectivity activity greater than 300x.

[0413] Test Example 2 Pharmacokinetic Determination in Mice

[0414] 1. Research Objectives:

[0415] Balb / c mice were used as test animals to study the pharmacokinetic behavior of the compound of the present invention in mice (plasma) after oral administration.

[0416] 2 Experimental plan

[0417] 2.1 Investigational Drugs:

[0418] The compound of the present invention is homemade.

[0419] 2.2 Experimental Animals

[0420] Each group contained 3 male Balb / c mice.

[0421] 2.3 Drug preparation:

[0422] Oral administration drug preparation: 0.5% CMC-Na (1% Tween 80)

[0423] Weigh 0.5 g of sodium carboxymethylcellulose (CMC-Na, viscosity: 800-1200 cps), dissolve it in 99 mL of purified water, and add 1 mL of Tween 80. Mix well to form a clear solution.

[0424] Example 1 and Example 2 were weighed and dissolved in the solution, shaken and ultrasonicated for 15 minutes to obtain a colorless clear solution with a concentration of 0.5 mg / mL.

[0425] Intravenous drug preparation: 5% DMSO + 10% Solutol HS15 + 85% PBS

[0426] The compound of the present invention was weighed and first added with 5% DMSO in proportion to the total volume of the compound to be administered. The mixture was vortexed and sonicated for 2 minutes to completely dissolve. Then, 10% Solutol HS15 was added and vortexed and sonicated for 2 minutes to completely dissolve the compound. Finally, 85% PBS was added and vortexed and sonicated for 5 minutes. The solution was filtered through a 0.22 μm filter to obtain a colorless, transparent, clear solution with a concentration of 0.2 mg / mL.

[0427] 2.4 Administration:

[0428] Balb / c mice (3 males per group) were fasted overnight and PO-administered at a dose of 5 mg / kg in a volume of 10 mL / kg.

[0429] Balb / c mice (3 males per group) were fasted overnight and administered IV at a dose of 1 mg / kg in a volume of 5 mL / kg.

[0430] 2.5 Sample collection:

[0431] Before administration and at 0.25 h, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 6.0 h, 8.0 h, and 24.0 h after administration, 0.04 mL of blood was collected from the experimental animals' orbits, placed in EDTA-2K tubes, and centrifuged at 8000 rpm at 4°C for 6 min to separate the plasma, which was then stored at -80°C. The animals were fed 4 h after administration.

[0432] 3 Experimental results: The final determination results were obtained using the LCMS / MS method

[0433] *Indicates F is approximately 100%.

[0434] The experimental results showed that the compounds of the present invention exhibited good metabolic properties, exposure AUC and maximum blood concentration C max All performed well, and the compounds had very good bioavailability.

[0435] Test Example 3 Ki determination

[0436] The G-402 cell line was used as a host cell to express (transiently or stably) enzymes of the human CYP11 family. Specifically, G-402 cell lines stably expressing human CYP11B1 and human CYP11B2 were established. To determine the inhibition constants of the test compounds against CYP11B2, cells were incubated for 16 hours at varying substrate concentrations (CYP11B2 cell line: 0.125-4 μM 11-DOC; CYP11B1 cell line: 0.3125-12 μM 11-deoxycortisol) and inhibitor concentrations (CYP11B2 cell line: 0-100 nM; CYP11B1 cell line: 0-10,000 nM). Product levels (aldosterone for CYP11B2 cell line; cortisol for CYP11B1 cell line) were quantified using CisBio's homogeneous time-resolved fluorescence (HTRF) assay. The Ki (Ki) was determined using the fitting algorithm provided by the GraphPad Prism program.

[0437] The compounds of the present invention have better affinity for CYP11B2 and greater selectivity for CYP11B1 than 200 times, and preferably greater than 500 times.

[0438] Test Example 4 In vivo drug efficacy determination

[0439] Male cynomolgus monkeys were orally administered the test compound (PO) and divided into 0 mpk (vehicle), 0.03 mpk, 0.1 mpk, 0.3 mpk, 1 mpk, and 3 mpk dose groups. One hour later, each group received an intravenous (IV) injection of 5 μg / kg ACTH. Blood samples (approximately 0.5 mL) were collected at -1 hour, 0 hour, 0.5 hour, 1.0 hour, 1.5 hour, 2 hours, and 3 hours after the IV ACTH injection. Samples were centrifuged (3200 g, 10 minutes at 2 to 8°C) within one hour of collection, and plasma aldosterone, cortisol, corticosterone, 11-deoxycortisol, and 11-deoxycorticosterone were analyzed by LC / MS-MS at each time point.

[0440] The compound of the present invention can effectively reduce the content of aldosterone at a low dose without causing significant changes in hormones such as cortisol.

[0441] Test Example 5 Monkey Pharmacokinetic Determination

[0442] 1. Research objectives:

[0443] Cynomolgus monkeys were used as test animals to study the pharmacokinetic behavior of the compound of the present invention in cynomolgus monkeys (plasma) at a dose of 3 mg / kg after oral administration.

[0444] 2. Experimental plan:

[0445] 2.1 Experimental drugs:

[0446] The compounds of the present invention were prepared in-house.

[0447] 2.2 Experimental Animals

[0448] Each group contained 3 male cynomolgus monkeys.

[0449] 2.3 Preparation prescription:

[0450] Oral administration drug preparation: 0.5% CMC-Na (1% Tween 80)

[0451] Weigh 0.50 g of sodium carboxymethyl cellulose (CMC-Na, viscosity: 800-1200 cps), dissolve it in 99 mL of purified water, add 1 ml of Tween 80, and mix and stir to form a clear solution.

[0452] The compound of Example 1 was weighed into a 100 mL glass bottle, and the solution was added. The mixture was vortexed and sonicated for 10 minutes to obtain a white suspension with a concentration of 0.6 mg / mL.

[0453] 2.4 Administration:

[0454] Three male cynomolgus monkeys were fasted overnight and then administered orally at a dose of 3 mg / kg in a volume of 5 mL / kg.

[0455] 2.5 Sample collection:

[0456] Blood collection: 0.3 mL of blood was collected from the forelimb vein of cynomolgus monkeys before administration and 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. The blood was placed in EDTA-K2 anticoagulant tubes, centrifuged at 6000 rpm for 6 minutes at 4°C to separate plasma, and stored at -80°C. The monkeys were fed 4 hours after administration.

[0457] 2.6 Sample processing:

[0458] 1) 40 μL of plasma sample was added to 160 μL of acetonitrile for precipitation, mixed, and centrifuged at 3500×g for 5-20 minutes.

[0459] 2) The supernatant solution after treatment was subjected to LC / MS / MS analysis to determine the concentration of the test compound. The LC / MS / MS analysis instrument was AB Sciex API 4000 Qtrap.

[0460] 2.7 Liquid phase analysis:

[0461] Liquid phase conditions: Shimadzu LC-20AD pump

[0462] ●Chromatographic column: Agilent ZORBAXX DB-C18 (50×2.1mm, 3.5μm) Mobile phase: Liquid A is 0.1% formic acid in water, Liquid B is acetonitrile

[0463] Flow rate: 0.4 mL / min

[0464] Elution time: 0-4.0 minutes, eluent is as follows:

[0465] 3 Experimental results:

[0466] The experimental results showed that the compounds of the present invention exhibited good metabolic properties, exposure AUC and maximum blood concentration C max All performed well.

[0467] Test Example 6: Pharmacokinetic Determination in Dogs

[0468] 1. Research objectives:

[0469] Beagle dogs were used as test animals to study the pharmacokinetic behavior of the compound of the present invention in beagle dogs (plasma) at a dose of 2 mg / kg after oral administration.

[0470] 2. Experimental plan:

[0471] 2.1 Experimental drugs:

[0472] The compounds of the present invention were prepared in-house.

[0473] 2.2 Experimental Animals

[0474] Beagle dogs (3 per group, male) were purchased from Weifang Shengnuo Experimental Animal Breeding Co., Ltd. (animal production license number: SCXK(Lu)20230001).

[0475] 2.3 Preparation prescription:

[0476] Oral drug preparation: 0.5% CMC-Na

[0477] Weigh 0.50 g of sodium carboxymethyl cellulose (CMC-Na, viscosity: 800-1200 cps), dissolve it in 100 mL of purified water, and mix and stir to form a clear solution.

[0478] The compound of the present invention was weighed and placed in a 100 mL glass bottle, and the solution was added thereto. The mixture was vortexed and sonicated for 10 minutes to obtain a white suspension with a concentration of 0.4 mg / mL.

[0479] 2.4 Administration:

[0480] Three male beagle dogs were fasted overnight and then administered orally at a dose of 2 mg / kg in a volume of 5 mL / kg.

[0481] 2.5 Sample collection:

[0482] Blood collection: 0.3 mL of blood was collected from the forelimb vein of beagle dogs before and 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration, and placed in EDTA-K2 anticoagulant tubes. Plasma was separated by centrifugation for 6 minutes before and after administration, and stored at -80°C; food was taken 4 hours after administration.

[0483] 2.6 Sample processing:

[0484] 1) Plasma sample: 40 μg of sample was added to 160 μg of sample and precipitated with acetonitrile. The mixture was mixed and centrifuged at 3500°C for 5-20 minutes.

[0485] 2) The supernatant solution after treatment was subjected to LC / MS / MS analysis to determine the concentration of the test compound. The LC / MS / MS analysis instrument was AB Sciex API 4000 Qtrap.

[0486] 2.7 Liquid phase analysis:

[0487] Liquid phase conditions: Shimadzu LC-20AD pump

[0488] Chromatographic column: Agilent ZORBAX XDB-C18 (50×2.1mm, 3.5μm) Mobile phase: Liquid A is 0.1% formic acid in water, Liquid B is acetonitrile

[0489] Flow rate: 0.4 mL / min

[0490] Elution time: 0-4.0 minutes, eluent is as follows:

[0491] The experimental results show that the compound of the present invention exhibits good metabolic properties and high bioavailability.

[0492] Test Example 7 Cell Permeability Test

[0493] 1. Research objectives:

[0494] The compounds of the invention were tested for bidirectional permeability across the Caco-2 cell model to assess whether they were transported by efflux transporters.

[0495] 2. Compounds and test materials:

[0496] 2.1 The test compound was prepared into a 10 mM stock solution with DMSO (or other suitable solution) and stored at -20°C until use.

[0497] 2.2 Control compounds: Atenolol, Metoprolol, and Erythromycin were prepared as 10 mM stock solutions for use.

[0498] 2.3 Caco-2 cells (Cell Bank, Chinese Academy of Sciences), PBS (Gibco, pH 7.4), HBSS (Gibco), DMEM medium (Gibco), Lucifer Yellow (Sigma), HEPES (Sigma).

[0499] 2.4 Prepare transport buffer containing 10 mM HBSS by mixing 1 mL of 1 M HEPES and 99 mL of HBSS.

[0500] 2.5 Take 100 mL of transporter buffer and 100 μL of 20 mM lucifer yellow solution to prepare a 20 μM lucifer yellow working solution.

[0501] 2.6 Preparation of compound working solution: Add 1 μL of compound stock solution to 999 μL of Lucifer Yellow working solution for a final concentration of 10 μM. Adjust the ratio and final concentration appropriately based on the properties of the compound.

[0502] 3. Experimental plan:

[0503] 3.1 Construction of Caco-2 cell permeability model

[0504] Resuscitate Caco-2 cells and select cells from passages 35 to 40 to construct a permeability model. Dilute Caco-2 cells in good condition to 1.0*10 5 cell / cm 2 Add 26 mL of DEME medium to the bottom plate and 400 μL of cell dilution to each sample well. Replace the medium every 2 to 3 days. Observe cell growth and measure TEER values ​​at appropriate times.

[0505] 3.2 Compound permeability test

[0506] 1) Aspirate the culture medium from the sample wells, add 400 μL of transport buffer, add 800 μL to each well of the receiving plate, and rinse 2 to 3 times.

[0507] 2) Add the compound working solution and transport buffer to the dosing end and the receiving end respectively. Add 400uL of compound working solution or transport buffer to each sample well and 800uL of compound working solution or transport buffer to each well of the bottom plate.

[0508] 3) Take 10 uL of compound working solution, add 90 uL of transport buffer to dilute 10 times, and add 200 uL of acetonitrile containing internal standard to stop, which is used as the working solution for the dosing end (D end) at T0.

[0509] 4) Incubate in a 37°C, 5% CO2 incubator for 90 min.

[0510] 5) Take 10uL of sample from the dosing end (D end), add 90uL of transport buffer to dilute 10 times, and add 200uL of acetonitrile containing internal standard to terminate the reaction. This is used as the working solution for the dosing end (D end) at T90.

[0511] 6) Take 100uL of sample from the A to B receiving end (R end) and add 200uL of acetonitrile containing the internal standard to terminate the reaction; take 100uL of sample from the B to A receiving end (R end) and add 200uL of acetonitrile containing the internal standard to terminate the reaction.

[0512] 7) Take 20 μL of the apical sample and add 100 μL of transport buffer; take 120 μL of the basolateral sample and measure the fluorescence intensity at the excitation / emission spectrum of 425 / 528 nm.

[0513] 8) Discard the apical and basolateral working solutions, add 400 μL of acetonitrile containing the internal standard to the apical side, and let it sit for 30 minutes to lyse the cells. Take 100 μL of the lysate and add 200 μL of acetonitrile containing the internal standard to measure the sample concentration.

[0514] 9) Centrifuge the sample at 3500 rpm for 10 min and take the supernatant for LC-MS / MS analysis.

[0515] 4. Experimental results:

[0516] The experimental results show that the compound of the present invention exhibits high permeability and no efflux in CaCo-2, and has excellent properties.

[0517] Test Example 8 Pharmacokinetic Determination in Rats

[0518] 1. Research objectives:

[0519] SD rats were used as test animals to study the pharmacokinetic behavior of the compound of the present invention in rats (plasma) after oral administration.

[0520] 2. Experimental Plan

[0521] 2.1 Investigational Drugs:

[0522] The compound of the present invention is homemade.

[0523] 2.2 Experimental Animals

[0524] Each group contained 3 male SD rats.

[0525] 2.3 Drug preparation:

[0526] Oral administration drug preparation: 0.5% CMC-Na (1% Tween 80)

[0527] Weigh 5g of sodium carboxymethylcellulose (CMC-Na, viscosity: 800-1200 cps), dissolve it in 1000mL of purified water, and add 10g of Tween 80. Mix well to form a clear solution.

[0528] The example compound was weighed and dissolved in the solution, shaken and sonicated for 15 minutes to obtain a colorless clear solution with a concentration of 0.5 mg / mL.

[0529] Intravenous drug preparation: 5% DMSO + 10% Solutol HS15 + 85% PBS

[0530] The example compound was weighed and first added with 5% DMSO in proportion to the total volume of the compound to be administered. The mixture was vortexed and sonicated for 2 minutes to completely dissolve it. Then, 10% Solutol HS15 was added and vortexed and sonicated for 2 minutes to completely dissolve it. Finally, 85% PBS was added and vortexed and sonicated for 5 minutes. The solution was filtered through a 0.22 μm filter to obtain a colorless, transparent, clear solution with a concentration of 0.2 mg / mL.

[0531] 2.4 Administration:

[0532] Three male SD rats were administered PO after overnight fasting at a dose of 5 mg / kg in a dosing volume of 10 mL / kg.

[0533] Three male SD rats were administered IV after overnight fasting at a dose of 1 mg / kg in a volume of 5 mL / kg.

[0534] 2.5 Sample collection:

[0535] Before administration and at 0.25 h, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 6.0 h, 8.0 h, and 24.0 h after administration, 0.2 mL of blood was collected from the jugular vein of the experimental animals, placed in EDTA-2K test tubes, and centrifuged at 8000 rpm at 4°C for 6 min to separate the plasma, which was then stored at -80°C. The animals were fed 4 h after administration.

[0536] 3 Experimental results: The final determination results were obtained using the LCMS / MS method

Claims

1. A compound represented by general formula (I'), its stereoisomer or a pharmaceutically acceptable salt thereof: in: is a single bond or a double bond; Ring A is phenyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl or absent; Ring B is a 4-7 membered heterocyclyl, a 5-6 membered heteroaryl or a phenyl group; Ring C is selected from the following groups: M1', M2', M4', M5', M6' are each independently selected from N, NH or CH; M3' is a bond, N or CH; R1 is independently selected from cycloalkyl, heterocyclyl, cycloalkyloxy, heterocyclyloxy, cycloalkylamino, heterocyclylamino, cycloalkylthio, heterocyclylthio, -C(O)(CH2) n R b 、-NR a C(O)(CH2) n R b 、-O(CH2) n R b 、-NH(CH2) n R b 、-S(CH2) n R b 、-S(O)2(CH2) n R b 、-S(O)(NH)(CH2) n R b 、-NR a S(O)2(CH2) n R b 、-NR a S(O)(NH)(CH2) n R b or -NS(O)(CH2) n R a R b , optionally, the cycloalkyl, heterocyclyl, cycloalkyloxy, heterocyclyloxy, cycloalkylamino, heterocyclylamino, cycloalkylthio or heterocyclylthio is further substituted by one or more selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, -C(O)(CH2) n R b 、-S(O)2(CH2) n R b 、-S(O)(NH)(CH2) n R b 、-S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b is substituted by a substituent in; Alternatively, any two R1s and adjacent carbon atoms form a 3-8 membered cycloalkyl or 4-7 membered heterocyclic group, and optionally, the 3-8 membered cycloalkyl or 4-7 membered heterocyclic group is further substituted by an oxo group, -C(O)R b 、-NR a C(O)R b 、-S(O)2R b 、-S(O)(NH)R b 、-NR a S(O)2R b or -NR a S(O)(NH)R b replaced by; R a or R b Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, optionally, the cycloalkyl, aryl, heteroaryl or heterocyclyl is further substituted with one or more substituents selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl or -S(O)2alkyl; R2, R3 or R4 are each independently selected from hydrogen, deuterium, oxo, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR a C(O)(CH2) n R b or -C(O)NR a (CH2) n R b , which may optionally be further substituted; Alternatively, R2 and R3 form a 3-8 membered cycloalkyl, a 5-6 membered heteroaryl or a 4-7 membered heterocyclic group with adjacent atoms, and optionally the 3-8 membered cycloalkyl, the 5-6 membered heteroaryl or the 4-7 membered heterocyclic group is further substituted with one or more oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, halogen, substituted by a substituent in a halogenated alkoxy group or a hydroxyalkyl group; Alternatively, any two R2 form a 3-8 membered cycloalkyl, a 5-6 membered heteroaryl or a 4-7 membered heterocyclyl with adjacent atoms, and the 3-8 membered cycloalkyl, the 5-6 membered heteroaryl or the 4-7 membered heterocyclyl is optionally further substituted with one or more substituents selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy or hydroxyalkyl; Alternatively, R2 and R4 form a 5-14 membered cycloalkyl, a 5-14 membered heteroaryl or a 5-14 membered heterocyclyl with adjacent atoms, optionally wherein the 5-14 membered cycloalkyl, the 5-14 membered heteroaryl or the 5-14 membered heterocyclyl is further substituted with one or more substituents selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy or hydroxyalkyl; p, x, y and z are each independently selected from 1, 2, 3 or 4; n is selected from 0, 1, 2 or 3.

2. A compound represented by general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof: in: Ring A is selected from phenyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl or absent; Ring B is selected from 4-7 membered heterocyclyl, 5-6 membered heteroaryl or phenyl; M1, M2 or M3 are each independently selected from N or CR4; R1 is independently selected from cycloalkyl, heterocyclyl, cycloalkyloxy, heterocyclyloxy, cycloalkylamino, heterocyclylamino, cycloalkylthio, heterocyclylthio, -C(O)(CH2) n R b 、-NR a C(O)(CH2) n R b 、-O(CH2) n R b 、-NH(CH2) n R b 、-S(CH2) n R b 、-S(O)2(CH2) n R b 、-S(O)(NH)(CH2) n R b 、-NR a S(O)2(CH2) n R b 、-NR a S(O)(NH)(CH2) n R b or -NS(O)(CH2) n R a R b , optionally, the cycloalkyl, heterocyclyl, cycloalkyloxy, heterocyclyloxy, cycloalkylamino, heterocyclylamino, cycloalkylthio or heterocyclylthio is further substituted by one or more selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, -C(O)(CH2) n R b 、-S(O)2(CH2) n R b 、-S(O)(NH)(CH2) n R b 、-S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b is substituted by a substituent in; R a or R b Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, optionally, the cycloalkyl, aryl, heteroaryl or heterocyclyl is further substituted with one or more substituents selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl or -S(O)2alkyl; R2, R3 or R4 are each independently selected from hydrogen, deuterium, oxo, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR a C(O)(CH2) n R b or -C(O)NR a (CH2) n R b , which may optionally be further substituted; Alternatively, R2 and R3 form a 3-8 membered cycloalkyl, a 5-6 membered heteroaryl or a 4-7 membered heterocyclic group with adjacent atoms, and the 3-8 membered cycloalkyl, the 5-6 membered heteroaryl or the 4-7 membered heterocyclic group is optionally further substituted with one or more selected from oxo, deuterium, substituted by a substituent of halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy or hydroxyalkyl; x, y and z are each independently selected from 0, 1, 2, 3 or 4; n is selected from 0, 1, 2 or 3.

3. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Ring A is selected from a 5-7 membered heterocyclic group or a 5-6 membered heteroaryl group containing 1-3 groups selected from C(O), N, O, S, SO2 or SONH.

4. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Ring B is selected from phenyl, containing 1-3 5-7 membered heterocyclic groups or 5-6 membered heteroaryl groups selected from C(O), N, O or S.

5. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Selected from 6. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R1 is each independently selected from 3-10 membered cycloalkyl, 4-10 membered heterocyclyl, 3-8 membered cycloalkyloxy, 4-8 membered heterocyclyloxy, 3-8 membered cycloalkylamino, 4-8 membered heterocyclylamino, 3-8 membered cycloalkylthio, 4-8 membered heterocyclylthio, -C(O)(CH2) n R b 、-NR a C(O)(CH2) n R b 、-O(CH2) n R b 、-NH(CH2) n R b 、-S(CH2) n R b 、-S(O)2(CH2) n R b 、-S(O)(NH)(CH2) n R b 、-NR a S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b Optionally, the 3-10 membered cycloalkyl, 4-10 membered heterocyclyl, 3-8 membered cycloalkyloxy, 4-8 membered heterocyclyloxy, 3-8 membered cycloalkylamino, 4-8 membered heterocyclylamino, 3-8 membered cycloalkylthio, 4-8 membered heterocyclylthio are further substituted by one or more selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, -C(O)(CH2) n R b 、-S(O)2(CH2) n R b 、-S(O)(NH)(CH2) n R b 、-S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b is substituted by a substituent in; R a or R b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 hydroxyalkyl, 3-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 selected from C(O), N, O or S, or 1-3 selected from C(O), N, O or S 4-8 membered heterocyclic group, optionally, the 3-8 membered cycloalkyl, the 5-8 membered heteroaryl containing 1-3 selected from C (O), N, O or S or the 4-8 membered heterocyclic group containing 1-3 selected from C (O), N, O or S, further substituted by one or more selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1- 6-deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, 3-6 membered cycloalkyl or -SO2-C 1-6 The alkyl group is substituted by a substituent.

7. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R1 is independently selected from 3-8 membered cycloalkyl, 4-8 membered heterocyclyl containing 1-3 selected from N, O, S, SO2 or SONH, 3-8 membered cycloalkyloxy, 3-8 membered cycloalkylamino, 4-8 membered heterocyclyloxy containing 1-3 selected from N, O, S, SO2 or SONH, 4-8 membered heterocyclylamino containing 1-3 selected from N, O, S, SO2 or SONH, -C(O)(CH2) n R b 、-NR a C(O)(CH2) n R b 、-O(CH2) n R b 、-S(O)2(CH2) n R b 、-S(O)(NH)(CH2) n R b 、-NR a S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b , optionally, the 3-8 membered cycloalkyl, the 4-8 membered heterocyclyl containing 1-3 selected from N, O, S, SO2 or SONH, the 3-8 membered cycloalkyloxy, the 3-8 membered cycloalkylamino, the 4-8 membered heterocyclyloxy containing 1-3 selected from N, O, S, SO2 or SONH or the 4-8 membered heterocyclylamino containing 1-3 selected from N, O, S, SO2 or SONH is further substituted with one or more selected from oxo, -C(O)(CH2) n R b 、-S(O)2(CH2) n R b 、-S(O)(NH)(CH2) n R b 、-S(O)2(CH2) n R b or -NR a S(O)(NH)(CH2) n R b is substituted by a substituent in; R a or R b are each independently selected from hydrogen, deuterium, C 1-3 The alkyl, 3-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 selected from N, O or S or 4-8 membered heterocyclic group containing 1-3 selected from C(O), N, O or S, optionally, the 5-8 membered heteroaryl containing 1-3 selected from N, O or S or 4-8 membered heterocyclic group containing 1-3 selected from C(O), N, O or S is further substituted by one or more selected from oxo, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, 3-6 membered cycloalkyl or -SO2-C 1-3 The alkyl group is substituted by a substituent.

8. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R2, R3 or R4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2- 6-alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Deuterated alkoxy, C 1-6 Hydroxyalkyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkyloxy, 3-8 membered cycloalkylamino, C 6-10 aryl, 5-6 membered heteroaryl containing 1-3 selected from N, O, S or 4-8 membered heterocyclic group containing 1-3 selected from C(O), N, O or S, -NR a R b 、-NR a C(O)R b or -C(O)NR a R b ; Preferably, R2, R3 or R4 are each independently selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl or C 3-6 Cycloalkyloxy.

9. The compound according to any one of claims 1 to 8, its stereoisomer or a pharmaceutically acceptable salt thereof, further being a compound represented by general formula (Ia) to (Ih), its stereoisomer or a pharmaceutically acceptable salt thereof: M1, M2 or M3 are each independently selected from N or CH; R1 is each independently selected from NR a C(O)R b , 3-8 membered cycloalkyl, 4-8 membered heterocyclyl containing 1-3 selected from N, O, S, SO2 or SONH, 3-8 membered cycloalkyloxy, 4-8 membered heterocyclyloxy containing 1-3 selected from N, O, S, SO2 or SONH; R2 is each independently selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl or C 3-6 Cycloalkyl; R a Selected from hydrogen, deuterium, C 1-3 Alkyl or C 1-3 Deuterated alkyl; R b Selected from hydrogen, deuterium, C 1-3 Alkyl, C 1-3 deuterated alkyl, 3-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 selected from N, O or S, or 4-8 membered heterocyclic group containing 1-3 selected from C(O), N, O, S, SO2 or SONH, optionally, the C 1-3 alkyl, 3-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 selected from N, O or S, or 4-8 membered heterocyclic group containing 1-3 selected from C(O), N, O, S, SO2 or SONH, further substituted by hydroxyl, amino, CN, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Substituted with hydroxyalkyl or 3-6 membered cycloalkyl; y is 1, 2, or 3.

10. The compound according to any one of claims 1 to 8, its stereoisomer or a pharmaceutically acceptable salt thereof, further being a compound represented by general formula (II-a) to (II-m), its stereoisomer or a pharmaceutically acceptable salt thereof: in: M4 are each independently selected from O or CH2; R1 is each independently selected from -C(O)R b 、-NR a C(O)R b 、-OR b 、-S(O)2R b 、-S(O)(NH)R b 、-NR a S(O)2R b 、-NR a S(O)(NH)R b or a 4-8 membered nitrogen-containing heterocyclic group, wherein the 4-8 membered nitrogen-containing heterocyclic group is optionally further -C(O)R b or -S(O)2R b replaced by; R a or R b are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 3-8 cycloalkyl, 5-8 membered heteroaryl containing 1-3 selected from N, O or S, or 4-8 membered heterocyclic group containing 1-3 selected from C(O), N, O or S, optionally, the hydroxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 A halogenated alkoxy group, a 3- to 8-membered cycloalkyl group, a 5- to 8-membered heteroaryl group containing 1-3 groups selected from N, O or S, or a 4- to 8-membered heterocyclic group containing 1-3 groups selected from C(O), N, O or S, further substituted with hydroxyl, amino, CN, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Substituted with hydroxyalkyl or 3-6 membered cycloalkyl; R2 is each independently selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl or C 3-6 Cycloalkyl.

11. Any of the following compounds, their stereoisomers or pharmaceutically acceptable salts thereof:

12. A pharmaceutical composition comprising a therapeutically effective dose of a compound according to any one of claims 1 to 11, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

13. Use of a compound according to any one of claims 1 to 11 or a pharmaceutical composition according to claim 12 in the preparation of a medicament for treating or preventing chronic kidney disease, renal or cardiac fibrosis, diabetic nephropathy, congestive heart failure, hypertension, primary aldosteronism and Cushing's syndrome; preferably, the hypertension is refractory hypertension.

14. Use of the compound of the general formula as shown in any one of claims 1 to 11, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition as claimed in claim 12 in the preparation of a drug for treating diseases related to CYP11B2.

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